Fused Pentacyclic Imidazole Derivatives

ABSTRACT

A series of fused pentacyclic imidazole derivatives, being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders. In particular, the present invention is concerned with 6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one derivatives and analogs thereof.

The present invention relates to classes of fused pentacyclic imidazolederivatives, and to their use in therapy. More particularly, thisinvention is concerned with pharmacologically active substituted fusedpentacyclic benzimidazole derivatives and analogs thereof. Inparticular, the present invention is concerned with6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-onederivatives and analogs thereof.

These compounds are modulators of the signalling of TNFα, and areaccordingly of benefit as pharmaceutical agents, especially in thetreatment of adverse inflammatory and autoimmune disorders, neurologicaland neurodegenerative disorders, pain and nociceptive disorders,cardiovascular disorders, metabolic disorders, ocular disorders, andoncological disorders.

TNFα is the prototypical member of the Tumour Necrosis Factor (TNF)superfamily of proteins that share a primary function of regulating cellsurvival and cell death. One structural feature common to all knownmembers of the TNF superfamily is the formation of trimeric complexesthat bind to, and activate, specific TNF superfamily receptors. By wayof example, TNFα exists in soluble and transmembrane forms and signalsthrough two receptors, known as TNFR1 and TNFR2, with distinctfunctional endpoints.

Various products capable of modulating TNFα activity are alreadycommercially available. All are approved for the treatment ofinflammatory and autoimmune disorders such as rheumatoid arthritis andCrohn's disease. All currently approved products are macromolecular andact by inhibiting the binding of human TNFα to its receptor. Typicalmacromolecular TNFα inhibitors include anti-TNFα antibodies; and solubleTNFα receptor fusion proteins. Examples of commercially availableanti-TNFα antibodies include fully human antibodies such as adalimumab(Humira®) and golimumab (Simponi®), chimeric antibodies such asinfliximab (Remicade®), and pegylated Fab′ fragments such ascertolizumab pegol (Cimzia®). An example of a commercially availablesoluble TNFα receptor fusion protein is etanercept (Enbrel®).

TNF superfamily members, including TNFα itself, are implicated in avariety of physiological and pathological functions that are believed toplay a part in a range of conditions of significant medical importance(see, for example, M. G. Tansey & D. E. Szymkowski, Drug DiscoveryToday, 2009, 14, 1082-1088; and F. S. Carneiro et al., J. SexualMedicine, 2010, 7, 3823-3834).

The compounds in accordance with the present invention, being potentmodulators of human TNFα activity, are therefore beneficial in thetreatment and/or prevention of various human ailments. These includeautoimmune and inflammatory disorders; neurological andneurodegenerative disorders; pain and nociceptive disorders;cardiovascular disorders; metabolic disorders; ocular disorders; andoncological disorders.

In addition, the compounds in accordance with the present invention maybe beneficial as pharmacological standards for use in the development ofnew biological tests and in the search for new pharmacological agents.Thus, in one embodiment, the compounds of this invention may be usefulas radioligands in assays for detecting pharmacologically activecompounds. In an alternative embodiment, certain compounds of thisinvention may be useful for coupling to a fluorophore to providefluorescent conjugates that can be utilised in assays (e.g. afluorescence polarisation assay) for detecting pharmacologically activecompounds.

International patent applications WO2013/186229A1, WO2014/009295A1 andWO2014/009296A1 relate to fused imidazole derivatives which aremodulators of the signalling of TNFα.

International patent applications WO2015/086525 and WO2015/086526published Jun. 18, 2015 relate to fused tricyclic imidazole derivativeswhich are modulators of the signalling of TNFα.

None of the prior art available to date, however, discloses or suggeststhe precise structural class of fused pentacyclic imidazole derivativesas provided by the present invention.

The present invention provides a compound of formula (I) or an N-oxidethereof, or a pharmaceutically acceptable salt thereof:

wherein

—X-Q- represents —O—, —O—C(O)—, —C(O)—O—, —O—C(CH—CN)—, —S—, —SO—,—SO₂—, —N(R^(g))—, —N(R^(f))—CO—, —CO—N(R^(f))—, —N(R^(f))—SO₂—,—SO₂—N(R^(f))—, —S(O)(NR^(f))—, —CH₂—CH₂—, —O—CH₂—, —CH₂—O—, —S—CH₂—,—SO—CH₂—, —SO₂—CH₂—, CH₂—S—, —CH₂—SO—, —CH₂—SO₂—, —N(R^(g))—CH₂—,—CH₂—N(R^(g))—, —S(O)(NR^(f))—CH₂—, —CH₂—S(O)(NR^(f))—,—N(R^(f))—C(S)—,—N═S(O)(CH₃)—O—C(═CH₂)— or —S(═N—CN)—, any of which groups may beoptionally substituted by one or more substituents.

Z represents methylene;

E represents a fused heteroaromatic ring system selected from the groupsof formula (Ea), (Eb) and (Ec),

wherein the asterisk (*) represents the site of attachment of E to theremainder of the molecule;

R¹ represents hydrogen, halogen, cyano, trifluoromethyl,trifluoromethoxy, —OR^(a), —SR^(a), —SOR^(a), —SO₂R^(a), —NR^(b)R^(c),—NR^(c)COR^(d), —NR^(c)CO₂R^(d), —NHCONR^(b)R^(c), —NR^(c)SO₂R^(e),—COR^(d), —CO₂R^(d), —CONR^(b)R^(c), —SO₂NR^(b)R^(c), or—S(O)(N—R^(b))R^(e); or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl,aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl,heteroaryl, heteroaryl(C₁₋₆)alkyl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents; or R¹ represents(C₃₋₇)heterocycloalkenyl-aryl-, which group may be optionallysubstituted by one or more substituents;

R² represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl,trifluoromethoxy or —OR^(a); or C₁₋₆ alkyl optionally substituted by oneor more substituents;

R³ and R⁴ independently represent hydrogen,halogen or trifluoromethyl;or C₁₋₆ alkyl, optionally substituted by one or more substituents;

R⁵ and R⁸ independently represent hydrogen, halogen, hydroxy, cyano,trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OR^(a), or C₁₋₆alkylsulphonyl; or C₁₋₆ alkyl optionally substituted by one or moresubstituents;

R⁶ and R⁷ independently represent hydrogen, halogen, trifluoromethyl,C₁₋₆ alkyl or C₁₋₆ alkoxy;

R¹² represents hydrogen or C₁₋₆ alkyl;

R^(a) represents C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl,aryl, aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any of whichgroups may be optionally substituted by one or more substituents;

R^(b) and R^(c) independently represent hydrogen or trifluoromethyl; orC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents;or

R^(b) and R^(c), when taken together with the nitrogen atom to whichthey are both attached, represent a heterocyclic moiety selected fromazetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl,thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl,homomorpholin-4-yl, homopiperazin-1-yl, (imino)(oxo)thiazinan-4-yl,(oxo)thiazinan-4-yl and (dioxo)thiazinan-4-yl, any of which groups maybe optionally substituted by one or more substituents;

R^(d) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇heterocycloalkyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents;

R_(e) represents C₁₋₆ alkyl, aryl or heteroaryl, any of which groups maybe optionally substituted by one or more substituents;

R^(f) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, or C₃₋₇heterocycloalkyl, any of which groups may be optionally substituted byone or more substituents; and

R^(g) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, —CO—(C₁₋₆)alkyl, or —SO₂—(C₁₋₆)alkyl, any of whichgroups may be optionally substituted by one or more substituents; orR^(g) represents —CO—(C₃₋₇)heterocycloalkyl, —SO₂—(C₃₋₇)cycloalkyl,—SO₂—(C₃₋₇)heterocycloalkyl, —SO₂-aryl or —SO₂-heteroaryl, any of whichgroups may be optionally substituted by one or more substituents; orR^(g) represents heteroaryl or (C₂₋₆)alkoxycarbonyl, either of whichgroups may be optionally substituted by one or more substituents.

The present invention also provides a compound of formula (I) as definedabove or an N-oxide thereof, or a pharmaceutically acceptable saltthereof, for use in therapy.

In another aspect, the present invention also provides a compound offormula (I) as defined above or an N-oxide thereof, or apharmaceutically acceptable salt thereof, for use in the treatmentand/or prevention of disorders for which the administration of amodulator of TNFα function is indicated.

In another aspect, the present invention provides a compound of formula(I) as defined above or an N-oxide thereof, or a pharmaceuticallyacceptable salt thereof for use in the treatment and/or prevention of aninflammatory or autoimmune disorder, a neurological or neurodegenerativedisorder, pain or a nociceptive disorder, a cardiovascular disorder, ametabolic disorder, an ocular disorder, or an oncological disorder.

In antoher aspect, the present invention provides for the use of acompound of formula (I) as defined above, or an N-oxide thereof, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament useful for the treatment and/or prevention of disorders forwhich the administration of a modulator of TNFα function is indicated.

In another aspect, the present invention provides for the use of acompound of formula (I) as defined above, or an N-oxide thereof, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament useful for the treatment of an inflammatory or autoimmunedisorder, a neurological or neurodegenerative disorder, pain or anociceptive disorder, a cardiovascular disorder, a metabolic disorder,an ocular disorder, or an oncological disorder.

The present invention also provides a method for the treatment and/orprevention of disorders for which the administration of a modulator ofTNFα function is indicated which comprises administering to a patient inneed of such treatment an effective amount of a compound of formula (I)as defined above, or an N-oxide thereof, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method for thetreatment and/or prevention of an inflammatory or autoimmune disorder, aneurological or neuro-degenerative disorder, pain or a nociceptivedisorder, a cardiovascular disorder, a metabolic disorder, an oculardisorder, or an oncological disorder, which comprises administering to apatient in need of such treatment an effective amount of a compound offormula (I) as defined above or an N-oxide thereof, or apharmaceutically acceptable salt thereof.

Where any of the groups in the compounds of formula (I) above is statedto be optionally substituted, this group may be unsubstituted, orsubstituted by one or more substituents. Typically, such groups will beunsubstituted, or substituted by one or two substituents. Suitablesubstitutents for each particular groups of compounds formula (I) arefurther described here after in the present specification.

The present invention includes within its scope salts of the compoundsof formula (I) above. For use in medicine, the salts of the compounds offormula (I) will be pharmaceutically acceptable salts. Other salts may,however, be useful in the preparation of the compounds of use in theinvention or of their pharmaceutically acceptable salts. Standardprinciples underlying the selection and preparation of pharmaceuticallyacceptable salts are described, for example, in Handbook ofPharmaceutical Salts: Properties, Selection and Use, ed. P. H. Stahl &C. G. Wermuth, Wiley-VCH, 2002.

The present invention includes within its scope solvates of thecompounds of formula (I) above. Such solvates may be formed with commonorganic solvents or water.

The present invention also includes within its scope co-crystals of thecompounds of formula (I) above. The technical term “co-crystal” is usedto describe the situation where neutral molecular components are presentwithin a crystalline compound in a definite stoichiometric ratio. Thepreparation of pharmaceutical co-crystals enables modifications to bemade to the crystalline form of an active pharmaceutical ingredient,which in turn can alter its physicochemical properties withoutcompromising its intended biological activity (see Pharmaceutical Saltsand Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

The present invention includes within its scope N-oxides of compounds offormula (I) above. Particular examples of N-oxides according to thepresent invention include pyrimidine N-oxide and pyridine N-oxide asillustrated in the Examples.The term “alkyl” as used herein refers toaliphatic hydrocarbon groups which may be straight or branched and maycomprise 1 to 20 carbon atoms in the chain, suitably 1 to 15 carbonatoms in the chain, more suitably 1 to 10 carbon atoms in the chain.Suitable alkyl groups which may be present on the compounds of use inthe invention include straight-chained and branched C₁₋₆ alkyl groups,for example C₁₋₄ alkyl groups. Illustrative alkyl goups include methyland ethyl groups, and straight-chained or branched propyl, butyl andpentyl groups. Suitable alkyl groups include methyl, ethyl, n-propyl,and isopropyl. Derived expressions such as “C₁₋₆ alkoxy”, “C₁₋₆alkylthio”, “C₁₋₆ alkylsulphonyl” and “C₁₋₆ alkylamino” are to beconstrued accordingly.

The term “C₃₋₇ cycloalkyl” as used herein refers to monovalent groups of3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon.Suitable C₃₋₇ cycloalkyl groups may comprise benzo-fused analoguesthereof. Illustrative C₃₋₇ cycloalkyl groups include cyclopropyl,cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl andcyclo heptyl.

The term “C₄₋₉ bicycloalkyl” as used herein refers to monovalent groupsof 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon.The term “C₄₋₇ cycloalkenyl” as used herein refers to monovalent groupsof 4 to 7 carbon atoms derived from a partially unsaturated monocyclichydrocarbon. Illustrative C₄₋₇cycloalkenyl groups include cyclobutenyl,cyclopentenyl, cyclohexenyl and cycloheptenyl.

The term “aryl” as used herein, refers to an unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g. phenyl) or multiple condensed rings (e.g. naphthyl). Illustrativearyl groups include phenyl.

Illustrative aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl andphenylpropyl.

The term “C₃₋₇ heterocycloalkyl” as used herein refers to saturatedmonocyclic rings containing 3 to 7 carbon atoms and at least oneheteroatom selected from oxygen, sulphur and nitrogen, and may comprisebenzo-fused analogues thereof. Illustrative heterocycloalkyl groupsinclude oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo-furanyl,dihydrobenzothienyl, pyrrolidinyl, indolinyl, dihydroisoindolinyl,isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydro-thiopyranyl,piperidinyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl,1,2,3,4-tetrahydroquinoxalinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl,morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl,diazepanyl, thiadiazepanyl, azocanyl, (imino)(oxo)thiazinanyl,(oxo)thiazinanyl, (dioxo)thiazinanyl, tetrahydrothiophenyl,(oxo)tetrahydrothiophenyl, (dioxo)tetrahydrothiophenyl and(oxo)thiomorpholinyl.

The term “C₃₋₇ heterocycloalkenyl” as used herein refers tomonounsaturated or polyunsaturated monocyclic rings containing 3 to 7carbon atoms and at least one heteroatom selected from oxygen, sulphurand nitrogen, and may comprise benzo-fused analogues thereof.Illustrative heterocycloalkenyl groups include thiazolinyl,imidazolinyl, dihydropyranyl,dihydrothiopyranyl,1,2,3,6-tetrahydropyridinyl, 1,2-dihydropyridinyl and1,2-dihydropyrimidinyl. The term “C₄₋₉ heterobicycloalkyl” as usedherein refers to a C₄₋₉ bicycloalkyl as defined herein, wherein one ormore of the carbon atoms have been replaced by one or more heteroatomsselected from oxygen, sulphur and nitrogen. Illustrativeheterobicycloalkyl groups include 3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,2-oxabicyclo[2.2.2]octanyl, quinuclidinyl,2-oxa-5-azabicyclo-[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl,3-oxa-7-azabicyclo[3.3.1]nonanyl and 3,9-diazabicyclo[4.2.1]nonanyl.Illustrative heterobicycloalky groups additionally include3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl.

The term “C₄₋₉ spiroheterocycloalkyl” as used herein refers to saturatedbicyclic ring systems containing 4 to 9 carbon atoms and at least oneheteroatom selected from oxygen, sulphur and nitrogen, in which the tworings are linked by a common atom. Illustrative spiroheterocycloalkylgroups include 5-azaspiro[2.3]hexanyl, 5-azaspiro-[2.4]heptanyl,2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro- [3.4]octanyl, 2-oxa-6-azaspiro[3.5]nonanyl,7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl and2,4,8-triazaspiro[4.5]decanyl.

The term “heteroaryl” as used herein represents aromatic carbocyclicgroups of from 5 to 14 carbon atoms having a single ring or multiplecondensed rings, wherein one or more of the said carbon atoms have beenreplaced by one or more heteroatoms selected from oxygen, sulphur andnitrogen. Illustrative heteroaryl groups include furyl, benzofuryl,dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl,thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl,2,3-dihydro-1H-isoindolyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl,pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl,4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl,thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl,imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl,imidazo[4,5-b]pyridinyl, purinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl,[1,2,4]triazolo[1,5-a]pyrimidinyl, benzotriazolyl, tetrazolyl,pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl,cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl,quinoxalinyl, pteridinyl, triazinyl and chromenyl groups.

The term “halogen” as used herein is intended to include fluorine,chlorine, bromine and iodine atoms, typically fluorine, chlorine orbromine atoms.

Where the compounds of formula (I) have one or more asymmetric centres,they may accordingly exist as enantiomers. Where the compounds of use inthe invention possess two or more asymmetric centres, they mayadditionally exist as diastereomers. The invention is to be understoodto extend to the use of all such enantiomers and diastereomers, and tomixtures thereof in any proportion, including racemates. Formula (I) andthe formulae depicted hereinafter are intended to represent allindividual stereoisomers and all possible mixtures thereof, unlessstated or shown otherwise. In addition, compounds of formula (I) mayexist as tautomers, for example keto (CH₂C═O)↔enol (CH═CHOH) tautomersor amide (NHC═O)↔hydroxyimine (N═COH) tautomers. Formula (I) and theformulae depicted hereinafter are intended to represent all individualtautomers and all possible mixtures thereof, unless stated or shownotherwise.

An illustrative example of a tautomer in accordance with the presentinvention, is 2-oxo-(1H)-pyridinyl which is a tautomer of2-hydroxy-pyridinyl.

Another illustrative example of a tautomer in accordance with thepresent invention, is 2-oxo-(1H)-pyrimidinyl which is a tautomer of2-hydroxy-pyrimidinyl.

A particular sub-class of compounds in accordance with the presentinvention is the sub-class of compounds of formula (IA), or an N-oxidethereof, or a pharmaceutically acceptable salt thereof,

wherein E, Z, —X-Q-, R₅, R⁶, R⁷ R⁸ and R¹² are as defined above.

It is to be understood that each individual atom present in formula (I),or in the formulae depicted hereinafter, may in fact be present in theform of any of its naturally occurring isotopes, with the most abundantisotope(s) being preferred. Thus, by way of example, each individualhydrogen atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹H, ²H (deuterium) or ³H (tritium)atom, preferably ¹H. Similarly, by way of example, each individualcarbon atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹²C, ¹³C or ¹⁴C atom, preferably ¹²C.

Generally, —X-Q- represents —O—, —O—C(O)—, —C(O)—O—, —O—C(CH—CN)—, —S—,—SO—, —SO₂—, —N(R^(g))—, —N(R^(f))—CO—, —CO—N(R^(f))—, —N(R^(f))—SO₂—,—SO₂—N(R^(f))—, —S(O)(NR^(f))—, —CH₂—CH₂—, —O—CH₂—, —CH₂—O—, —S—CH₂—,—SO—CH₂—, —SO—CH₂—, —SO₂—CH₂—, CH₂—S—, —CH₂—SO—, —CH₂—SO₂—,—N(R^(g))—CH₂—, —CH₂—N(R^(g))—, —S(O)(NR^(f))—CH₂—, —CH₂—S(O)(NR^(f))—,—N(R^(f))—C(S)—, —N═S(O)(CH₃)—, —O—C(═CH₂)— or —S(═N—CN)—, any of whichgroups may be substituted by one or more substituents.

More generally, —X-Q- represents —O—, —O—C(O)—, —C(O)—O—, —C(O)—O—,—O—C(CH—CN)—, —S—, —SO—, —SO₂—, —N(R^(g))—, —N(R^(f))—CO—,—CO—N(R^(f))—, —N(R^(f))—SO₂—, —SO₂—N(R^(f))—, —S(O)(NR^(f))—,—CH₂—CH₂—, —O—CH₂—, —CH₂—O—, —S—CH₂—, —SO—CH₂—, —SO₂—CH₂—, CH₂—S—,—CH₂—SO—, —CH₂—SO₂—, —N(R^(g))—CH₂—, —CH₂—N(R^(g))—, —S(O)(NR^(f))—CH₂—,—CH₂—S(O)(NR^(f))— or —N(R^(f))—C(S)—.

Typically, —X-Q- represents —O—, —O—C(O)—, —C(O)—O—, —O—C(CH—CN)—, —S—,—SO—, —SO₂—, —N(R^(g))—, —N(R^(f))—CO—, —CO—N(R^(f))—, —N(R^(f))—SO₂—,—SO₂—N(R^(f))—, —S(O)(NR^(f))—, —CH₂—CH₂—, —O—CH₂—, —CH₂—O—, —S—CH₂—,—SO—CH₂—, —SO₂—CH₂—, CH₂—S—, —CH₂—SO—, —CH₂—SO₂—, —N(R^(g))—CH₂—,—CH₂—N(R^(g))—, —S(O)(NR^(f))—CH₂— or —CH₂—S(O)(NR^(f))—.

In a first embodiment, —X-Q- represents —O—. In a second embodiment,—X-Q- represents —O—C(O)—. In a third embodiment according to theinvention, —X-Q- represents —C(O)—O—. In a fourth embodiment, —X-Q-represents —O—C(CH—CN)—. In a fifth embodiment, —X-Q- represents —S—. Ina sixth embodiment, —X-Q- represents —SO—. In a seventh embodiment,—X-Q- represents —SO₂—. In an eighth embodiment, —X-Q- represents—N(R^(g))—. In a ninth embodiment, —X-Q- represents —N(R^(f))—CO—. In atenth embodiment, —X-Q- represents —CO—N(R^(f))—. In an eleventhembodiment, —X-Q- represents —N(R^(f))—SO₂—. In a twelfth embodiment,—X-Q- represents —SO₂—N(R^(f))—. In a thirteenth embodiment, —X-Q-represents —S(O)(NR^(f))—. In a fourteenth embodiment, —X-Q- representsoptionally substituted —CH₂—CH₂—. In one aspect of that embodiment,—X-Q- represents —CH₂—CH₂—. In a fifteenth embodiment, —X-Q-represents—optionally substituted —O—CH₂—. In one aspect of thatembodiment, —X-Q- represents —O—CH₂—. In a sixteenth embodiment, —X-Q-represents optionally substituted —CH₂—O—. In one aspect of thatembodiment, —X-Q- represents —CH₂—O—. In a seventeenth embodiment, —X-Q-represents optionally substituted —S—CH₂—. In one aspect of thatembodiment, X-Q- represents —S—CH₂—. In an eighteenth embodiment, —X-Q-represents optionally substituted —SO-CH₂—. In one aspect of thatembodiment, —X-Q- represents —SO-CH₂—. In a nineteenth embodiment, —X-Q-represents optionally substituted —SO₂—CH₂—. In one aspect of thatembodiment, —X-Q- represents —SO₂—CH₂—. In a twentieth embodiment, —X-Q-represents optionally substituted —CH₂—S—. In one aspect of thatembodiment, X-Q- represents optionally substituted —CH₂—S—. In atwenty-first embodiment, —X-Q- represents optionally substituted—CH₂—SO—. In one aspect of that embodiment, —X-Q- represents —CH₂—SO—.In a twenty-second embodiment, —X-Q- represents optionally substituted—CH₂—SO₂—. In one aspect of that embodiment, —X-Q- represents —CH₂—SO₂—.In a twenty-third embodiment, —X-Q- represents optionally substituted—N(R^(g))—CH₂—. In one aspect of that embodiment, —X-Q- represents—N(R^(g))—CH₂—. In a twenty-fourth embodiment, —X-Q- representsoptionally substituted —CH₂—N(R^(g))—. In one aspect of that embodiment,—X-Q- represents —CH₂—N(R^(g))—. In a twenty-fifth embodiment, —X-Q-represents optionally substituted —S(O)(NR^(f))—CH₂—. In one aspect ofthat embodiment, —X-Q- represents —S(O)(NR^(f))—CH₂—. In a twenty-sixthembodiment, —X-Q- represents optionally substituted —CH₂—S(O)(NR^(f))—.In one aspect of that embodiment, —X-Q- represents —CH₂—S(O)(NR^(f))—.In a twenty-seventh embodiment, —X-Q- represents —N(R^(f))—C(S)—. In atwenty-eighth embodiment, —X-Q- represents —N═S(O)(CH₃). In atwenty-ninth embodiment, —X-Q- represents —O—C(═CH₂)—. In a thirtiethembodiment —X-Q- represents —S(═N—CN)—. Typical substituents on —X-Q-include halogen, (C₁₋₆)alkyl and carboxy. Additional substituents on—X-Q- include trifluoromethyl. Further substituents on —X-Q-include(C₂₋₆)alkylcarbonyl, (C₂₋₆)alkoxycarbonyl, and hydroxy(C₁₋₆)alkyl.

Particular examples of substituents on —X-Q- include fluoro, methyl,carboxy, trifluoromethyl, methylcarbonyl, deuterated methyl,ethoxycarbonyl, hydroxyisopropyl, and hydroxymethyl.

Suitable substituents on —X-Q- include fluoro, methyl and carboxy.

Appropriately, —X-Q- represents —O—, —O—C(O)—, —O—C(CH—CN)—, —S—, —SO—,—SO₂—; or —N(R^(g))—, —N(R^(f))—CO—, —N(R^(f))—SO₂—, O—CH₂—, -, CH₂—S—,—CH₂—SO—, —CH₂—SO₂—, —N(R^(g))—CH₂—, —N(R^(f))—C(S)—, —N═S(O)(CH₃)—,—O—C(═CH₂)— or —S(═N—CN)—, any of which groups may be optionallysubstituted.

Particularly, —X-Q- represents —O—, —O—C(O)-, —O—C(CH—CN)—, —S—, —SO—,—SO₂—, —N(R^(g))—, —N(R^(f))—CO—, —N(R^(g))—CH₂—, or —N(R^(f))—C(S)—,any of which groups may be optionally substituted.

Suitably, —X-Q- represents —O—, —O—C(O)—, —O—C(CH—CN)—, —N(R^(g))—,—N(R^(f))—CO—, —N(R^(g))—CH₂—, or —N(R^(f))—C(S)—.

Typically, —X-Q- represents —N(R^(f))—C(O)—, —O—C(O)— or —O—C(CH—CN)—.

Appositely, —X-Q- represents —N(R^(f))—C(O)—.

Generally, Z represents methylene.

Generally, E represents a fused heteroaromatic ring system of formula(Ea) or a fused heteroaromatic ring system of formula (Eb).

In a first embodiment according to the present invention, E represents afused heteroaromatic ring system of formula (Ea).

In a second embodiment according to the present invention, E representsa fused heteroaromatic ring system of formula (Eb).

In a third embodiment according to the present invention, E represents afused heteroaromatic ring system of formula (Ec).

Particular sub-classes of compounds in accordance with the presentinvention include compounds of formula (IB), (IC), and (ID).

wherein —X-Q-, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹² are as definedabove.

Particular sub-classes of compounds in accordance with the presentinvention include compounds of formula (IB) and (IC), wherein —X-Q-, Z,R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸ and R¹² are as defined above.

A particular sub-class of compounds in accordance with the presentinvention is the sub-class of compounds of formula (IB), wherein —X-Q-,Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹² are as defined above.

A further particular sub-class ofcompounds in accordance with thepresent invention is the sub-class of compounds of formula (IC), wherein—X-Q-, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ , R⁸ and R¹² are as defined above.

Generally, R¹ represents hydrogen, halogen, or cyano; or aryl, C₃₋₇heterocycloalkyl, heteroaryl, (C₃₋₇)cycloalkyl-heteroaryl,(C₃₋₇)heterocycloalkyl-heteroaryl, (C₄₋₉)bicycloalkyl-heteroaryl,(C₄₋₉)heterobicycloalkyl-heteroaryl-,(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkenyl, or(C₃₋₇)heterocycloalkenyl-aryl-, any of which groups may be optionallysubstituted by one or more substituents.

Typically, R¹ represents hydrogen, halogen, or cyano; or aryl, C₃₋₇heterocycloalkyl, heteroaryl, (C₃₋₇)cycloalkyl-heteroaryl,(C₃₋₇)heterocycloalkyl-heteroaryl, (C₄₋₉)bicycloalkyl-heteroaryl,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

More typically, R¹ represents halogen or cyano; or aryl, heteroaryl,(C₃₋₇)cycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl-heteroaryl,(C₄₋₉)heterobicycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl ,(C₃₋₇)heterocycloalkenyl, or (C₃₋₇)heterocycloalkenyl-aryl, any of whichgroups may be optionally substituted by one or more substituents.

Even more typically, R¹ represents halogen or cyano; or aryl,heteroaryl, (C₃₋₇)cycloalkyl-heteroaryl,(C₃₋₇)heterocycloalkyl-heteroaryl, or(C₄₋₉)heterobicycloalkyl-heteroaryl any of which groups may beoptionally substituted by one or more substituents.

Particularly, R¹ represents hydrogen, halogen or cyano; or aryl,heteroaryl, (C₃₋₇)heterocycloalkyl-heteroaryl, any of which groups maybe optionally substituted by one or more substituents.

More particularly, R¹ represents halogen or cyano; or aryl, heteroaryl,or (C₃₋₇)cycloalkyl-heteroaryl, any of which groups may be optionallysubstituted by one or more substituents.

Suitably, R¹ represents hydrogen; or R¹ represents aryl or heteroaryl,either of which groups may be optionally substituted by one or moresubstituents.

Appositely, R¹ represents aryl or heteroaryl, either of which groups maybe optionally substituted by one or more substituents.

More suitably, R¹ represents heteroaryl, either of which groups may beoptionally substituted by one or more substituents.In a firstembodiment, R¹ represents hydrogen.

In a second embodiment, R¹ represents halogen. In one aspect of thatembodiment, R¹ represents bromo. In another aspect of that embodiment,R¹ represents chloro.

In a third embodiment, R¹ represents cyano.

In a fourth embodiment, R¹ represents optionally substituted aryl. Inone aspect of that embodiment, R¹ represents optionally substitutedphenyl.

In fifth embodiment, R¹ represents optionally substituted C₃₋₇heterocycloalkyl. In one aspect of that embodiment, R¹ representsazetidinyl.

In a sixth embodiment, R¹ represents optionally substituted heteroaryl.In one aspect of that embodiment, R¹ represents optionally substitutedpyrimidinyl. In another aspect of that embodiment, R¹ representsoptionally substituted pyridinyl.

In a seventh embodiment, R¹ represents optionally substituted(C₃₋₇)cycloalkyl-heteroaryl-. In a first aspect of that embodiment, R¹represents optionally substituted cyclohexylpyrazolyl-. In a secondaspect of that embodiment, R¹ represents optionally substitutedcyclohexylpyridinyl-. In a third aspect of that embodiment, R¹represents optionally substituted cyclopropylpyrimidinyl-. In a fourthaspect of that embodiment, R¹ represents optionally substitutedcyclobutylpyrimidinyl-. In a fifth aspect of that embodiment, R¹represents optionally substituted cyclopentylpyrimidinyl-. In a sixthaspect of that embodiment, R¹ represents optionally substitutedcyclohexylpyrimidinyl-. In a seventh aspect of that embodiment, R¹represents optionally substituted cyclohexyl-pyrazinyl-. In an eighthaspect of that embodiment, R¹ represents optionally substitutedcyclopropylpyridinyl.

In an eighth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl-heteroaryl-. In a first aspect of thatembodiment, R¹ represents optionally substituted pyrrolidinylpyridinyl-.In a second aspect of that embodiment, R¹ represents optionallysubstituted tetrahydropyranylpyridinyl-. In a third aspect of thatembodiment, R¹ represents optionally substituted piperidinylpyridinyl-.In a fourth aspect of that embodiment, R¹ represents optionallysubstituted piperazinylpyridinyl-. In a fifth aspect of that embodiment,R¹ represents optionally substituted morpholinylpyridinyl-. In a sixthaspect of that embodiment, R¹ represents optionally substitutedthiomorpholinyl-pyridinyl-. In a seventh aspect of that embodiment, R¹represents optionally substituted diazepanylpyridinyl-. In an eighthaspect of that embodiment, R¹ represents optionally substitutedoxetanylpyrimidinyl-. In a ninth aspect of that embodiment, R¹represents optionally substituted azetidinylpyrimidinyl-. In a tenthaspect of that embodiment, R¹ represents optionally substitutedtetrahydrofuranylpyrimidinyl-. In an eleventh aspect of that embodiment,R¹ represents optionally substituted pyrrolidinylpyrimidinyl-. In atwelfth aspect of that embodiment, R¹ represents optionally substitutedtetrahydropyranyl-pyrimidinyl-. In a thirteenth aspect of thatembodiment, R¹ represents optionally substitutedpiperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R¹represents optionally substituted piperazinylpyrimidinyl-. In afifteenth aspect of that embodiment, R¹ represents optionallysubstituted morpholinylpyrimidinyl-. In a sixteenth aspect of thatembodiment, R¹ represents optionally substitutedthiomorpholinyl-pyrimidinyl-. In a seventeenth aspect of thatembodiment, R¹ represents optionally substituted azepanylpyrimidinyl-.In an eighteenth aspect of that embodiment, R¹ represents optionallysubstituted oxazepanylpyrimidinyl-. In a nineteenth aspect of thatembodiment, R¹ represents optionally substituted diazepanylpyrimidinyl-.In a twentieth aspect of that embodiment, R¹ represents optionallysubstituted thiadiazepanyl-pyrimidinyl-. In a twenty-first aspect ofthat embodiment, R¹ represents optionally substitutedoxetanylpyrazinyl-. In a twenty-second aspect of that embodiment, R¹represents optionally substituted piperidinylpyrazinyl-. In atwenty-third aspect of that embodiment, R¹ represents optionallysubstituted tetrahydropyranylpyridinyl-. In twenty-third aspect of thatembodiment, R¹ represents (imino)(oxo)thiazinanyl-pyrimidinyl-. Intwenty-fourth aspect of that embodiment, R¹ represents(oxo)thiazinanyl-pyrimidinyl-. In twenty-fifth aspect of thatembodiment, R¹ represents (dioxo)thiazinanyl-pyrimidinyl-. In atwenty-sixth aspect of that embodiment, R¹ represents substituted(dioxo)tetrahydrothiophenyl-pyrimidinyl-. In a twenty-seventh aspect ofthat embodiment, R¹ represents substitutedtetrahydrothiophenyl-pyrimidinyl-. In a twenty-eighth aspect of thatembodiment, R¹ represents substituted(dioxo)thiomorpholinyl-pyrimidinyl-. In a twenty-ninth aspect of thatembodiment, R¹ represents substituted azetidinyl-pyrazolyl. In athirtieth aspect of that embodiment, R¹ represents substituted(oxo)tetrahydrothiophenyl-pyrimidinyl. In a thirty-first aspect, R¹represents substituted (oxo)thiomorpholinyl.

In a ninth embodiment, R¹ represents optionally substituted(C₄₋₉)bicycloalkyl-heteroaryl-.

In a tenth embodiment, R¹ represents optionally substituted(C₄₋₉)-heterobicycloalkyl-heteroaryl-. In one aspect of that embodiment,R¹ represents optionally substituted(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-pyrimidinyl-. In a second aspectof this embodiment, R¹ represents optionally substituted(2-oxa-5-azabicyclo[2.2.1]heptanyl)-pyrimidinyl-. In a third aspect ofthat embodiment, R¹ represents optionally substituted(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-pyrimidinyl-. In a fourth aspect, R¹represents optionally substituted(3,6-diazabicyclo[3.2.2]nonanyl)-pyrimidinyl-.

In an eleventh embodiment, R¹ represents optionally substituted(C₄₋₉)-spiroheterocycloalkyl-heteroaryl-.

In a twelfth embodiment, R¹ represents optionally substituted(C₃₋₇)heterocycloalkenyl. In one aspect of that embodiment, R¹represents optionally substituted 1,2-dihydropyridinyl. In a secondaspect of that embodiment, R¹ represents optionally substituted1,2-dihydropyrimidinyl.

In a thirteenth embodiment, R¹ represents optionally substituted(C₃₋₇)heterocycloalkenyl-aryl. In one aspect of that embodiment, R¹represents optionally substituted imidazolyl-phenyl.

Typically, R¹ represents chloro or cyano; or phenyl, pyridinyl,pyrimidinyl, cyclopropyl-pyridinyl-, cyclobutyl-pyrimidinyl,cyclobutyl-pyridinyl-, cyclohexyl-pyrimidinyl-,(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-pyrimidinyl-,azetidinyl-pyrimidinyl-, azetidinyl-pyridinyl, pyrrolidinyl-pyridinyl-,pyrrolidinyl-phenyl-, piperazinyl-pyridinyl-, piperazinyl-pyrimidinyl-,pyrazolyl-, morpholinyl-pyrimidinyl-, thiomorpholinyl-pyrimidinyl-,(dioxo)thiomorpholinyl-pyrimidinyl-, (oxo)thiomorpholinyl-pyrimidinyl-,oxetanyl-pyridinyl-, oxetanyl-pyrimidinyl-, imidazolyl-phenyl,diazepanyl-pyrimidinyl-, (oxo)tetrahydrothiophenyl-pyrimidinyl-,(dioxo)tetrahydrothiophenyl-pyrimidinyl-,tetrahydrothiophenyl-pyrimidinyl azetidinyl-pyrazolyl-,(2-oxa-5-azabicyclo[2.2.1]heptanyl)-pyrimidinyl-,(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-pyrimidinyl-,(3,6-diazabicyclo[3.2.2]nonanyl)-pyrimidinyl-,tetrahydropyranyl-pyrimidinyl, azetidinyl, 1,2-dihydropyridinyl, or1,2-dihydropyrimidinyl, any of which groups may be optionallysubstituted by one or more substituents.

Particularly, R¹ represents hydrogen, chloro or cyano; or phenyl,pyridinyl, or pyrimidinyl, any of which groups may be optionallysubstituted by one or more substituents.

Illustratively, R¹ represents pyrimidinyl, which may be optionallysubstituted by one or more substituents.

Typical examples of optional substituents on R¹ include one, two orthree substituents independently selected from halogen, halo(C₁₋₆)alkyl,cyano, cyano(C₁₋₆)alkyl, nitro(C₁₋₆)alkyl, C₁₋₆ alkyl,phosphate(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, trifluoromethyl, trifluoroethyl,C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkyl, trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo,amino, amino-(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,(C₁₋₆)alkoxy(C₁₋₆)alkylamino,N-[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₁₋₆ alkylsulphonylamino,N-[(C₁₋₆)alkyl]—N-[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkyl-sulphonyl]amino,N-[(C₁₋₆)alkyl]—N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkyl-amino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₂₋₆)alkyl-carbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl-methylidenyl,aminocarbonyl, aminosulphonyl, (C₁₋₆)alkylsulphoximinyl and[(C₁₋₆)alkyl][N-(C₁₋₆)alkyl]sulphoximinyl. Additional examples ofoptional substituents on R¹ include C₁₋₆ alkyl phosphate-C₁₋₆ alkyl,sulphate-C₁₋₆ alkyl, carboxy(C₁₋₆)alkyl-carbonyloxy-C₁₋₆ alkyl, andphosphate-methoxy-C₁₋₆ alkyl. A further additional example of optionalsubstituent on R¹ include (C₂₋₆) alkoxycarbonyl-amino-C₁₋₆ alkyl.Additional optional substituents on R¹ include difluoromethyl,(C₁₋₆)alkyl-sulphinyl-amino-, di(C₁₋₆)alkylamino (C₁₋₆)alkyl,di(C₁₋₆)alkenylamino (C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl-amino-C₁₋₆ alkyl,and tetrahydrofuranyl.

Illustrative examples of optional substituents on R¹ include one, two orthree substituents independently selected from halogen, cyano,cyano(C₁₋₆)alkyl, C₁₋₆ alkyl, difluoromethyl, trifluoromethyl, hydroxy,(hydroxy)(C₁₋₆)alkyl, amino, (amino)(C₁₋₆) alkyl, C₁₋₆ alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkyl, C₂₋₆ alkylcarbonyl, C₂₋₆ alkoxycarbonyl, (C₂₋₆)alkoxycarbonyl-amino-C₁₋₆ alkyl, phosphate(C₁₋₆)alkyl, C₁₋₆ alkylthio ,C₁₋₆ alkylsulphonyl, oxo, (C₁₋₆)alkylsulphoximinyl,(C₁₋₆)alkylsulphinyl-amino-, di(C₁₋₆)alkylamino (C₁₋₆)alkyl,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, di(C₁₋₆)alkenylamino (C₁₋₆)alkyl,(C₂₋₆)alkylcarbonylamino (C₁₋₆)alkyl , C₁₋₆ alkylsulphonyl-amino-C₁₋₆alkyl, tetrahydrofuranyl, sulphate(C₁₋₆)alkyl, andcarboxy-(C₁₋₆)alkyl-carbonyloxy-(C₁₋₆)alkyl.

Particular examples of optional substituents on R¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl,trifluoromethyl, hydroxy, (hydroxy)(C₁₋₆) alkyl, (amino)(C₁₋₆) alkyl,C₁₋₆ alkoxy, (C₁₋₆) alkoxy(C₁₋₆)alkyl, (C₂₋₆) alkoxycarbonyl-amino-C₁₋₆alkyl, phosphate(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, oxo and(C₁₋₆)alkylsulphoximinyl.

Suitable examples of optional substituents on R¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl, hydroxy,(hydroxy)(C₁₋₆) alkyl, C₁₋₆ alkoxy, (C₁₋₆) alkoxy(C₁₋₆)alkyl,phosphate(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, oxo and (C1_(—)6)alkylsulphoximinyl.

Particular examples of optional substituents on R¹ include one, two orthree substituents independently selected from (hydroxy)(C₁₋₆) alkyl and(C₁₋₆) alkoxy(C₁₋₆)alkyl.

Typical examples of particular substituents on R¹ include one, two orthree substituents independently selected from fluoro, chloro,fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl,ethyl, isopropyl, phosphate-isopropyl, isopropylmethyl, cyclopropyl,cyclobutyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy,hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, methoxyisopropyl,trifluoro-ethoxy, carboxycyclobutyloxy, methylthio, methylsulphonyl,methylsulphonylmethyl, methylsulphonylethyl, oxo, amino, aminomethyl,aminoisopropyl, methylamino, dimethylamino, methoxyethylamino,N-(hydroxyethyl)-N-(methyl)amino, acetylaminomethyl,methylsulphonylamino, N-methyl-N-(methylsulphonyl)amino,bis(methylsulphonyl)amino, N-(carboxyethyl)-N-(methyl)amino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,acetoxyisopropyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl,ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, ethoxy-carbonylmethyl, ethoxycarbonylethyl,morpholinylethoxycarbonyl, ethoxycarbonyl-methylidenyl,methylsulphonylaminocarbonyl, acetylaminosulphonyl,methoxyamino-carbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, amino-sulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl. Additional typical examples of optionalsubstituents on R¹ include ethyl phosphate-isopropyl,sulphate-isopropyl, carboxy-ethyl-carbonyloxy-isopropyl, andphosphate-methoxy-isopropyl. A further additional typical example ofsubstituents on R¹ include (tert-butoxycarbonyl)amino-isopropyl. Otheradditional typical examples of susbtituents on R¹ include(tert-butyl)carbonyl, methoxycarbonylamino-isopropyl,dimethylaminoisopropyl, (tert-butyl)sulphinyl-amino,(tert-butyl)sulphonylamino, methylsulphonylaminoisopropyl,methylcarbonylamino-isopropyl, cyanoisopropyl, difluoromethyl,tetrahydrofuranyl, di(propenyl)aminoisopropyl and hydroxyisobutyl.

Appropriate examples of optional substituents on R¹ include one, two orthree substituents independently selected from methyl, difluoromethyl,trifluoromethyl, hydroxy, hydroxyisopropyl, methoxy, methoxyisopropyl,phosphate-isopropyl, (tert-butoxycarbonyl)amino-isopropyl,aminoisopropyl, dimethylaminoisopropyl, methyl-sulphonyl,methylsulphoximinyl, oxo, tert-butoxycarbonyl,(methoxycarbonyl)amino-isopropyl, methylthio,(tent-butypsulphinyl-amino, amino, (tent-butypsulphonyl-amino,methylsulphonylamino-isopropyl, methylcarbonylamino-isopropyl, fluoro,cyano, cyanoisopropyl, tetrahydrofuranyl, di(propenyl)aminoisopropyl,sulphate-isopropyl, carboxy-ethyl-carbonyloxy-isopropyl and(hydroxy)isobutyl.

Illustrative examples of optional substituents on R¹ include one, two orthree substituents independently selected from methyl, trifluoromethyl,hydroxy, hydroxyisopropyl, methoxy, methoxyisopropyl,phosphate-isopropyl, (tert-butoxycarbonyl)amino-isopropyl,aminoisopropyl, methyl-sulphonyl and methylsulphoximinyl.

Suitable examples of optional substituents on R¹ include one, two orthree substituents independently selected from methyl, hydroxy,hydroxyisopropyl, methoxy, methoxyisopropyl, phosphate-isopropyl,methyl-sulphonyl and methylsulphoximinyl.

Particular examples of substituents on R¹ include one, two or threesubstituents independently selected from hydroxyisopropyl andmethoxyisopropyl.

In a particular embodiment, R¹ is substituted by hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R¹ is substituted by hydroxyisopropyl. Ina particular aspect of that embodiment, R¹ is substituted by2-hydroxyprop-2-yl.

In another particular embodiment, R¹ is substituted by (C₁₋₆)alkoxy(C₁₋₆)alkyl. In one aspect of that embodiment, R¹ is substitutedby methoxyisopropyl. In a particular aspect of this embodiment, R¹ issubstituted by 2-methoxyprop-2-yl.

Illustrative values of R¹ include chloro, cyano, methylsulphonyl-phenyl,methylsulphoximinyl-phenyl, (dihydroxy)(methyl)cyclobutylpyrimidinyl,hydroxyisopropylpyridinyl, hydroxyisopropylpyrimidinyl,(methyl)(hydroxyisopropyl)pyrimidinyl, phosphate-isopropylpyrimidinyl,methoxypyridinyl, methoxyisopropylpyrimidinyl, 2-oxo-pyridin-(1H)-yl,(tert-butoxycarbonyl)aminoisopropyl-pyrimidinyl,aminoisopropylpyrimidinyl,(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-pyrimidinyl,(hydroxy)(trifluoromethyl)azetidinyl-pyrimidinyl,(methylsulphonyl)(methyl)phenyl, (methyl)(hydroxyisopropyl)pyridinyl,[(hydroxy)(trifluoromethyl)azetidinyl](methyl)pyrimidinylmethylsulphonylcyclopropylpyridinyl,(dimethyl)(hydroxyisopropyl)pyrimidinyl,(hydroxyisopropyl)(trifluoromethyl)pyrimidinyl,(tert-butoxycarbonyl)(hydroxy)pyrrolidine-pyridinyl,(hydroxy)pyrrolidine-pyridinyl,(methoxycarbonyl)aminoisopropyl-pyrimidinyl, piperazinylpyridinyl,(methylsulphonyl)piperazinyl-pyridinyl,(dimethylamino)isopropylpyrimidinyl, (oxo)piperazinylpyrimidinyl,(N-methyppyrazolyl, (methylthio)(methyl)phenyl, morpholinylpyrimidinyl,((tent-butyl)sulphinylamino)cyclobutylpyridinyl,(amino)cyclobutylpyridinyl,((tent-butypsulphinylamino)oxetanylpyridinyl, (amino)oxetanylpyridinyl,((tent-butypsulphonylamino)oxetanylpyridinyl, pyrrolidinylpyridinyl,(dimethyl)imidazolylphenyl, (methylsulphonyl)aminoisopropylpyrimidinyl,methylcarbonylaminoisopropylpyrimidinyl, pyrrolidinyl-phenyl,(oxo)diazepanylpyrimidinyl, (hydroxy)(methyl)azetidinyl-pyrimidinyl,thiomorpholinylpyrimidinyl, (oxo)thiomorpholinylpyrimidinyl,(dioxo)thiomorpholinylpyrimidinyl,(difluoro)(hydroxy)cyclohexylpyrimidinyl,(hydroxy)(oxo)tetrahydrothiophenyl-pyrimidinyl,(hydroxy)(dioxo)tetrahydrothiophenyl-pyrimidinyl,(hydroxy)tetrahydrothiophenyl-pyrimidinyl, (hydroxy)oxetanylpyrimidinyl,(methylsulphonyl)azetidinyl-2,5-pyrazolyl,(oxo)(methyl)-1,2-dihydropyridinyl, (oxo)-1,2-dihydropyrimidinyl,(dihydroxy)(methyl)cyclohexylpyrimidinyl, cyanoisopropylpyrimidinyl,(cyano)(methyl)azetidinylpyrimidinyl,(2-oxa-5-azabicyclo[2.2.1]heptanyl)-pyrimidinyl-,(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-pyrimidinyl-,(oxo)(3,6-diazabicyclo[3.2.2]nonanyl)-pyrimidinyl-,(hydroxyisopropyl)azetidinyl, (difluoro)azetidinylpyrimidinyl,tetrahydropyranylpyrimidinyl, methylsulphoxyminylpyridinyl,(difluoromethyl)(hydroxyisopropyl)pyrimidinyl,(tetrahydrofuranyl)(hydroxyisopropyl)pyrimidinyl,di(propenyl)aminoisopropylpyrimidinyl, sulphate-isopropylpyrimidinyl,carboxy-ethyl-carbonyloxy-isopropyl-pyrimidinyl and(hydroxy)isobutylpyrimidinyl.Specific values of R¹ include chloro,methylsulphonyl-phenyl, methylsulphoximinyl-phenyl,(dihydroxy)(methyl)cyclobutylpyrimidinyl, hydroxyisopropylpyridinyl,hydroxyisopropylpyrimidinyl, (methyl)(hydroxyisopropyl)pyrimidinyl,phosphate-isopropylpyrimidinyl, methoxypyridinyl,methoxyisopropylpyrimidinyl, 2-oxo-pyridin-(1H)-yl,(tert-butoxycarbonyl)aminoisopropyl-pyrimidinyl,aminoisopropylpyrimidinyl,(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-pyrimidinyl,(hydroxy)(trifluoromethyl)azetidinyl-pyrimidinyl,(methylsulphonyl)(methyl)phenyl and (methyl)(hydroxyisopropyl)pyridinyl.

Particular values of R¹ include methylsulphonyl-phenyl,methylsulphoximinyl-phenyl, (dihydroxy)(methyl)cyclobutylpyrimidinyl,hydroxyisopropylpyridinyl, hydroxyisopropylpyrimidinyl,(methyl)(hydroxyisopropyl)pyrimidinyl; phosphate-isopropylpyrimidinyl,methoxypyridinyl, methoxyisopropylpyrimidinyl and 2-oxo-pyridin-(1H)-yl.

Selected values of R¹ include hydroxyisopropylpyrimidinyl, particularly2-(2-hydroxy-propan-2-yl)-pyrimidin-5-yl; methoxyisopropylpyrimidinyl,particularly 2-(2-methoxy-propan-2-yl)-pyrimidin-5-yl;aminoisopropylpyrimidinyl, particularly2-(2-amino-propan-2-yl)-pyrimidin-5-yl; andphosphate-isopropylpyrimidinyl, particularly2-(2-phosphate-propane-2-yl)-pyrimidin-5-yl.

In one embodiment, R¹ represents2-(2-hydroxy-propan-2-yl)-pyrimidin-5-yl. In another embodiment, R¹represents 2-(2-amino-propan-2-yl)-pyrimidin-5-yl. In a furtherembodiment, R¹ represents 2-(2-phosphate-propane-2-yl)-pyrimidin-5-yl.

Illustrative values of R¹ include hydroxyisopropylpyrimidinyl,particularly 2-(2-hydroxy-propan-2-yl)-pyrimidin-5-yl, andmethoxyisopropylpyrimidinyl, particularly2-(2-methoxy-propan-2-yl)-pyrimidin-5-yl.

Typically, R² represents hydrogen, halogen, trifluoromethyl,trifluoromethoxy or —OR^(a); or C₁₋₆ alkyl optionally substituted by oneor more substituents.

Suitably, R² represents hydrogen or halogen.

In a first embodiment, R² represents hydrogen. In a second embodiment,R² represents halogen. In one aspect of that embodiment, R² representsfluoro. In another aspect of that embodiment, R² represents chloro. In athird embodiment, R² represents cyano. In a fourth embodiment, R²represents nitro. In a fifth embodiment, R² represents hydroxy. In asixth embodiment, R² represents trifluoromethyl. In a seventhembodiment, R² represents trifluoromethoxy. In an eighth embodiment, R²represents —OR^(a). In a ninth embodiment, R² represents optionallysubstituted C₁₋₆ alkyl. In a first aspect of that embodiment, R²represents C₁₋₆ alkyl. In a particular aspect of this embodiment, R²represents methyl. In another particular aspect of this embodiment, R²represents ethyl. In a second aspect of that embodiment, R² representsmonosubstituted methyl or monosubstituted ethyl.

Typical examples of optional substituents on R² include C₂₋₆alkoxycarbonyl.

Typical examples of particular substituents on R² includeethoxycarbonyl.

Typical values of R² include hydrogen, fluoro, chloro, trifluoromethyl,trifluoromethoxy, —OR^(a), methyl and ethoxycarbonylethyl.

Specific values of R² include hydrogen, bromo and fluoro.

Particular values of R² include hydrogen and fluoro.

Generally, R³ represents hydrogen, halogen, trifluoromethyl, or C₁₋₆alkyl.

Typically, R³ represents hydrogen, halogen or C₁₋₆ alkyl.

In a first embodiment, R³ represents hydrogen. In a second embodiment,R³ represents halogen. In one aspect of that embodiment, R³ representsfluoro. In a third embodiment, R³ represents optionally substituted C₁₋₆alkyl. In one aspect of that embodiment, R³ represents C₁₋₆ alkyl. In aparticular aspect of this embodiment, R³ represents methyl. In anotherparticular aspect of this embodiment, R³ represents ethyl. In a fourthembodiment, R³ represents trifluoromethyl.

Illustratively, R³ represents hydrogen or trifluoromethyl.

In a particular embodiment, R³ represents hydrogen.

Generally, R⁴ represents hydrogen, halogen , trifluoromethyl, or C₁₋₆alkyl.

Typically, R⁴ represents hydrogen, halogen or C₁₋₆ alkyl.

In a first embodiment, R⁴ represents hydrogen. In a second embodiment,R⁴ represents halogen. In one aspect of that embodiment, R⁴ representsfluoro. In a third embodiment, R⁴ represents optionally substituted C₁₋₆alkyl. In one aspect of that embodiment, R⁴ represents C₁₋₆ alkyl. In aparticular aspect of this embodiment, R⁴ represents methyl. In anotherparticular aspect of this embodiment, R⁴ represents ethyl. In a fourthembodiment, R⁴ represents trifluoromethyl.

Illustratively, R⁴ represents hydrogen or trifluoromethyl.

In a particular embodiment, R⁴ represents hydrogen.

Typically, R⁵ represents halogen, cyano, difluoromethoxy,trifluoromethoxy, —OR^(a), or C₁₋₆ alkylsulphonyl; or C₁₋₆ alkyloptionally substituted by one or more substituents.

Generally, R⁵ represents halogen, -ORB, difluoromethoxy ortrifluoromethoxy.

In a first embodiment, R⁵ represents hydrogen. In a second embodiment,R⁵ represents halogen. In one aspect of that embodiment, R⁵ representschloro. In a second aspect of that embodiment, R⁵ represents fluoro. Ina third embodiment, R⁵ represents cyano. In a fourth embodiment, R⁵represents hydroxy. In a fifth embodiment, R⁵ representstrifluoromethyl. In a sixth embodiment, R⁵ represents difluoromethoxy.In a seventh embodiment, R⁵ represents trifluoromethoxy. In an eighthembodiment, R⁵ represents —OR^(a). In one aspect of that embodiment, R⁵represents methoxy. In a ninth embodiment, R⁵ represents C₁₋₆alkylsulphonyl. In one aspect of that embodiment, R⁵ representsmethylsulphonyl. In a tenth embodiment, R⁵ represents optionallysubstituted C₁₋₆ alkyl. In one aspect of that embodiment, R⁵ representsC₁₋₆ alkyl. In a particular aspect of this embodiment, R⁵ representsmethyl. In another particular aspect of this embodiment, R⁵ representsethyl.

Suitably, R⁵ represents fluoro, methoxy, difluoromethoxy ortrifluoromethoxy.

Appositely, R⁵ represents fluoro, methoxy or difluoromethoxy.

Suitably, R⁵ represents difluoromethoxy.

Generally, R⁶ represents hydrogen, halogen or trifluoromethyl.

In a first embodiment, R⁶ represents hydrogen. In a second embodiment,R⁶ represents halogen. In one aspect of that embodiment, R⁶ representschloro. In a second aspect of that embodiment, R⁶ represents fluoro. Ina third aspect of that embodiment, R⁶ represents bromo. In a thirdembodiment, R⁶ represents trifluoromethyl. In a fourth embodiment, R⁶represents C₁₋₆ alkyl. In a first aspect of that embodiment, R⁶represents C₁₋₄ alkyl. In a second aspect of that embodiment R⁶represents C₁₋₃ alkyl. In a third aspect of that embodiment, R⁶represents C₁₋₂ alkyl. In a particular aspect of this embodiment, R⁶represents methyl. In another particular aspect of this embodiment, R⁶represents ethyl. In a fifth embodiment, R⁶ represents C₁₋₆ alkoxy. In aparticular aspect of that embodiment, R⁶ represents methoxy.

Particularly, R⁶ represents hydrogen, bromo or trifluoromethyl.

Illustratively, R⁶ represents hydrogen or bromo.

Suitably, R⁶ represents hydrogen.

In a first embodiment, R⁷ represents hydrogen. In a second embodiment,R⁷ represents halogen. In one aspect of that embodiment, R⁷ representschloro. In a second aspect of that embodiment, R⁷ represents fluoro. Ina third embodiment, R⁷ represents trifluoromethyl. In a fourthembodiment, R⁷ represents C₁₋₆ alkyl. In a first aspect of thatembodiment, R⁷ represents C₁₋₄ alkyl. In a second aspect of thatembodiment R⁷ represents C₁₋₃ alkyl. In a third aspect of thatembodiment, R⁷ represents C₁₋₂ alkyl. In a particular aspect of thisembodiment, R⁷ represents methyl. In another particular aspect of thisembodiment, R⁷ represents ethyl. In a fifth embodiment, R⁷ representsC₁₋₆ alkoxy. In a particular aspect of that embodiment, R⁷ representsmethoxy.

Illustratively, R⁷ represents hydrogen or trifluoromethyl.

Suitably, R⁷ represents hydrogen.

Generally, R⁸ represents hydrogen, halogen or trifluoromethyl.

In a first embodiment, R⁸ represents hydrogen. In a second embodiment,R⁸ represents halogen. In one aspect of that embodiment, R⁸ representschloro. In a second aspect of that embodiment, R⁸ represents fluoro. Ina third embodiment, R⁸ represents cyano. In a fourth embodiment, R⁸represents hydroxy. In a fifth embodiment, R⁸ representstrifluoromethyl. In a sixth embodiment, R⁸ represents difluoromethoxy.In a seventh embodiment, R⁸ represents trifluoromethoxy. In an eighthembodiment, R⁸ represents —OR^(a). In one aspect of that embodiment, R⁸represents methoxy. In a ninth embodiment, R⁸ represents C₁₋₆alkylsulphonyl. In one aspect of that embodiment, R⁸ representsmethylsulphonyl. In a tenth embodiment, R⁸ represents optionallysubstituted C₁₋₆ alkyl. In one aspect of that embodiment, R⁸ representsC₁₋₆ alkyl. In a particular aspect of this embodiment, R⁸ representsmethyl. In another particular aspect of this embodiment, R⁸ representsunsubstituted ethyl. In an eleventh embodiment, R⁸ representstrifluoromethyl.

Particularly, R⁸ represents hydrogen, chloro or trifluoromethyl

Illustratively, R⁸ represents hydrogen or chloro.

Suitably, R⁸ represents hydrogen.

Generally, R¹² represents hydrogen or C₁₋₆ alkyl.

Suitably, R¹² represents hydrogen or methyl.

Apositely, R¹² represents hydrogen.

Generally, R^(a) represents C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents.

Generally, R^(b) and R^(c) independently represent hydrogen ortrifluoromethyl; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl,any of which groups may be optionally substituted by one or moresubstituents; or

R^(b) and R^(c), when taken together with the nitrogen atom to whichthey are both attached, represent az etidin-1-yl, pyrrolidin-1-yl,oxazolidin-3-yl, isoxazo lidin-2-yl, thiazo lidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpho lin-4-yl, thiomorpholin-4-yl,piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, ho mop iperazin-1-yl, (imino)(oxo)thiazinan-4-yl, (oxo)thiazinan-4-yl or(dioxo)thiazinan-4-yl any of which groups may be optionally substitutedby one or more substituents.

Generally, R^(d) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl,aryl, C₃₋₇ heterocycloalkyl or heteroaryl, any of which groups may beoptionally substituted by one or more substituents.

Generally, R^(e) represents C₁₋₆ alkyl, aryl or heteroaryl, any of whichgroups may be optionally substituted by one or more substituents.

Typical examples of suitable substituents which may be present on R^(a),R^(b), R^(c), R^(d) or R^(e), or on the heterocyclic moiety—NR^(b)R^(c), include halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆alkylsulphinyl, C₁₋₆ alkylsulphonyl, hydroxy, hydroxy(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, cyano, trifluoromethyl, oxo, C₂₋₆ alkylcarbonyl,carboxy, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkylcarbonyloxy, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, phenylamino, pyridinylamino, C₂₋₆alkylcarbonylamino, C₂₋₆ alkylcarbonylamino(C₁₋₆)alkyl, C₂₋₆alkoxycarbonylamino, C₁₋₆ alkylsulphonylamino, aminocarbonyl, C₁₋₆alkylaminocarbonyl and di(C₁₋₆)alkylaminocarbonyl.

Typical examples of specific substituents which may be present on R^(a),R^(b), R^(c), R^(d), or R^(e), or on the heterocyclic moiety —NR^(b)Rc,include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy,isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl,methylthio, ethylthio, methylsulphinyl, methylsulphonyl, hydroxy,hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo,acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,acetoxy, amino, methylamino, ethylamino, dimethylamino, phenylamino,pyridinylamino, acetylamino, tert-butoxycarbonylamino,acetylaminomethyl, methylsulphonylamino, aminocarbonyl,methylaminocarbonyl and dimethylaminocarbonyl.

Suitably, R^(a) represents C₁₋₆ alkyl, aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents.

In a first embodiment, R^(a) represents optionally substituted C₁₋₆alkyl. In a first aspect of that embodiment, R^(a) represents C₁₋₆alkyl. In a particular aspect of this embodiment, R^(a) representsmethyl. In a second aspect of that embodiment, R^(a) representssubstituted C₁₋₆ alkyl. In a particular aspect of this embodiment, R^(a)represents methoxyethyl. In a second embodiment, R^(a) representsoptionally substituted aryl. In a first aspect of this embodiment, R^(a)represents aryl. In a particular aspect of this embodiment, R^(a)represents phenyl. In a second aspect of that embodiment, R^(a)represents monosubstituted aryl. In a particular aspect of thisembodiment, R^(a) represents methylphenyl. In a third embodiment, R^(a)represents optionally substituted aryl(C₁₋₆)alkyl. In one aspect of thatembodiment, R^(a) represents aryl(C₁₋₆)alkyl. In a particular aspect ofthis embodiment, R^(a) represents benzyl. In a fourth embodiment, R^(a)represents optionally substituted heteroaryl. In one aspect of thisembodiment, R^(a) represents heteroaryl. In a fifth embodiment, R^(a)represents optionally substituted heteroaryl(C₁₋₆)alkyl. In a particularaspect of this embodiment, R^(a) represents dioxoisoindolylpropyl. In asixth embodiment, R^(a) represents C₃₋₇ cycloalkyl. In a seventhembodiment, R^(a) represents C₃₋₇ heterocycloalkyl.

Appositely, R^(a) represents C₁₋₆ alkyl. Illustratively, R^(a)represents methyl.

Typically, R^(b) represents hydrogen; or C₁₋₆ alkyl, aryl(C₁₋₆)alkyl,C₃₋₇ heterocycloalkyl or C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, any of whichgroups may be optionally substituted by one or more substituents.

Suitably, R^(b) represents hydrogen or C₁₋₆ alkyl.

In a first embodiment, R^(b) represents hydrogen. In a secondembodiment, R^(b) represents C₁₋₆ alkyl. In a particular aspect of thatembodiment, R^(b) represents methyl.

Typically R^(c) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl orC₃₋₇ heterocycloalkyl, any of which groups may be optionally substitutedby one or more substituents.

Suitably, R^(c) represents hydrogen or C₁₋₆ alkyl.

In a first embodiment, R^(c) is hydrogen. In a second embodiment, R^(c)represents C₁₋₆ alkyl. In a one aspect of that embodiment, R^(c)represents methyl. In a another aspect of that embodiment, R^(c)represents ethyl.

Appositely, R^(c) represents hydrogen or ethyl.

Alternatively, the moiety —NR^(b)R^(c) may suitably representazetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl,thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl,homomorpholin-4-yl or homopiperazin-1-yl, (imino)(oxo)thiazinan-4-yl,(oxo)thiazinan-4-yl or (dioxo)thiazinan-4-yl, any of which groups may beoptionally substituted by one or more substituents.

Specific values of the heterocyclic moiety —NR^(b)R^(c) includeazetidin-1-yl, hydroxyazetidin-1-yl, hydroxymethylazetidin-1-yl,(hydroxy)(hydroxymethyl)azetidin-1-yl, aminomethyl-azetidin-1-yl,cyanoazetidin-1-yl, carboxyazetidin-1-yl, aminoazetidin-1-yl, aminocarbonylazetidin-1-yl, pyrrolidin-1-yl, aminomethylpyrrolidin-1-yl,oxopyrrolidin-1-yl, acetylaminomethylpyrrolidin-1-yl,tert-butoxycarbonylaminopyrrolidin-1-yl, oxo-oxazolidin-3-yl,hydroxyisoxazolidin-2-yl, thiazolidin-3-yl, oxothiazolidin-3-yl,dioxo-isothiazolidin-2-yl, piperidin-1-yl, hydroxypiperidin-1-yl,hydroxymethylpiperidin-1-yl, aminopiperidin-1-yl,acetylaminopiperidin-1-yl, tert-butoxycarbonylaminopiperidin-1-yl,methylsulphonylaminopiperidin-1-yl, morpholin-4-yl, piperazin-1-yl,methylpiperazin-1-yl, methylsulphonylpiperazin-1-yl, oxopiperazin-1-yl,acetylpiperazin-1-yl, ethoxycarbonylpiperazin-1-yl,oxohomopiperazin-1-yl, (imino)(oxo)thiazinan-4-yl, (oxo)thiazinan-4-yl,and (dioxo)thiazinan-4-yl.

Typically, R^(d) represents hydrogen; or C₁₋₆ alkyl, aryl or heteroaryl,any of which groups may be optionally substituted by one or moresubstituents.

Selected examples of suitable substituents on R^(d) include halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, C₂₋₆ alkylcarbonyloxy anddi(C₁₋₆)alkylamino.

Selected examples of particular substituents on R^(d) include fluoro,methyl, methoxy, oxo, acetoxy and dimethylamino.

Suitably, R^(d) represents hydrogen or C₁₋₆ alkyl.

In a first embodiment, R^(d) represents hydrogen. In a secondembodiment, R^(d) represents optionally substituted C₁₋₆ alkyl. In oneaspect of that embodiment, R^(d) represents C₁₋₆ alkyl. In a thirdembodiment, R^(d) represents optionally substituted aryl. In one aspectof that embodiment, R^(d) represents phenyl. In a fourth embodiment,R^(d) represents optionally substituted heteroaryl.

Appositely, R^(d) represents hydrogen or methyl.

Typically, R^(e) represents C₁₋₆ alkyl or aryl, either of which groupsmay be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(e) include C₁₋₆ alkyl,especially methyl.

In a first embodiment, R^(e) represents optionally substituted C₁₋₆alkyl. In a particular aspect of that embodiment, R^(e) represents C₁₋₆alkyl. In a particular aspect of this embodiment especially methyl. In asecond embodiment, R^(e) represents optionally substituted aryl. In oneaspect of that embodiment, R^(e) represents phenyl. In another aspect ofthat embodiment, R^(e) represents monosubstituted aryl.

Suitably, R^(e) represents methyl, propyl or methylphenyl.

Generally, R^(f) represents hydrogen; or C₁₋₆ alkyl, C₃₋₆ cycloalkyl, orC₄₋₆ heterocycloalkyl, any of which groups may be optionally substitutedby one or more substituents.

Suitably, R^(f) represents hydrogen; or C₁₋₆ alkyl, which group may beoptionally substituted by one or more substituents.

Generally, R^(g) represents hydrogen; or C₁₋₆ alkyl, —CO—(C₁₋₆)alkyl,—SO₂-(C₁₋₆)alkyl. —CO—(C₃₋₇)heterocycloalkyl, —SO₂-(C₃₋₇)cycloalkyl,—SO₂-(C₃₋₇)heterocycloalkyl, —SO₂-aryl, —SO₂-heteroaryl, heteroaryl or(C₂₋₆)alkoxycarbonyl, any of which groups may be optionally substitutedby one or more substituents.

More generally, R^(g) represents hydrogen; or C₁₋₆ alkyl,—CO—(C₁₋₆)alkyl, —SO₂-(C₁₋₆)alkyl. —CO—(C₃₋₇)heterocycloalkyl,—SO₂—(C₃₋₇)cycloalkyl, —SO₂-aryl, —SO₂-heteroaryl, heteroaryl or(C₂₋₆)alkoxycarbonyl, any of which groups may be optionally substitutedby one or more substituents.

Typically, R^(g) represents hydrogen; or C₁₋₆ alkyl, —CO—(C₁₋₆)alkyl,—SO₂-(C₁₋₆)alkyl. —CO—(C₃₋₇)heterocycloalkyl, —SO₂-(C₃₋₇)cycloalkyl,—SO₂—(C₃₋₇)heterocycloalkyl, —SO₂-aryl or —SO₂-heteroaryl, any of whichgroups may be optionally substituted by one or more substituents.

Interestingly, R^(g) represents hydrogen; or C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocycloalkyl, —CO—(C₁₋₆)alkyl, or —SO₂-(C₁₋₆)alkyl,any of which groups may be optionally substituted by one or moresubstituents.

Suitably, R^(g) represents hydrogen, optionally substituted C₁₋₆ alkyl,—CO—(C₁₋₆)alkyl or —SO₂-(C₁₋₆)alkyl.

Typically, substituents on R^(g) include independently halogen, C₁₋₆alkyl, carboxy and C₁₋₆ alkoxycarbonyl. Additional substituents on R^(g)include trifluoromethyl, C₄₋₉ heterobicycloalkyl, (C₁₋₆ alkyl)sulphonyl,tri(C₁₋₆ alkyl)silyloxy, hydroxy and (C₁₋₆)alkoxy.

Appositely, substituents on Wand R^(g) include independently halogen andC₁₋₆ alkyl.

Particular examples of substituents on R^(g) include independentlymethyl, trifluoromethyl, ethoxycarbonyl,3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl, methylsulphonyl,(tert-butyl)(di-methyl)silyloxyethyl, hydroxy and methoxy.

Particular examples of substituent on R^(f) include trifluoromethyl,carboxy and hydroxy.

In a first embodiment, R^(f) represents hydrogen. In a secondembodiment, R^(f) represents optionally substituted C₁₋₆ alkyl. In oneaspect of that embodiment, R^(f) represents C₁₋₆ alkyl. In a particularaspect of this embodiment, R^(f) represents methyl. In anotherparticular aspect of this embodiment, R^(f) represents ethyl. In afurther particular aspect of this embodiment, R^(f) representsisopropyl. In another aspect of that embodiment, R^(f) representsdeuterated methyl. In a further aspect of that embodiment, R^(f)represents substituted C₁₋₆ alkyl. In a third embodiment, R^(f)represents optionally substituted C₃₋₆ cycloalkyl. In one aspect of thatembodiment, R^(f) represents C₃₋₆ cycloalkyl.

Particular values of R^(f) include hydrogen, methyl, ethyl, isopropyl,(carboxy)methyl, (trifluoromethyl)methyl, (hydroxyisopropyl)methyl anddeuterated methyl.

Illustrative values of R^(f) include hydrogen, methyl, ethyl andisopropyl.

In a first embodiment, R^(g) represents hydrogen. In a secondembodiment, R^(g) represents optionally substituted C₁₋₆ alkyl. In oneaspect of that embodiment, R^(g) represents C₁₋₆ alkyl. In a particularaspect of this embodiment, R^(g) represents methyl. In anotherparticular aspect of this embodiment, R^(g) represents ethyl. In afurther particular aspect of this embodiment, R^(g) representsisopropyl. In a third embodiment, R^(g) represents optionallysubstituted C₃₋₆ cycloalkyl. In one aspect of that embodiment, R^(g)represents C₃₋₆cycloalkyl. In a fourth embodiment, R^(g) representsoptionally substituted —CO—(C₁₋₆)alkyl. In one aspect of thatembodiment, R^(g) represents —CO—(C₁₋₆)alkyl. In a particular aspect ofthis embodiment, R^(g) represents —CO—CH₃. In a fifth embodiment, R^(g)represents optionally substituted —SO₂-(C₁₋₆)alkyl. In one aspect ofthat embodiment, R^(g) represents —SO₂—(C₁₋₆)alkyl. In a particularaspect of this embodiment, R^(g) represents —SO₂—CH₃. In a sixthembodiment, R^(g) represents optionally substituted—CO—(C₃₋₇)heterocycloalkyl. In a particular aspect of that embodiment,R^(g) represents —CO-azetidinyl. In a seventh embodiment, R^(g)represents optionally substituted —SO₂-(C₃₋₇)cycloalkyl. In a particularaspect of that embodiment, R^(g) represents —SO₂-cyclopropyl. In aneighth embodiment, R^(g) represents optionally substituted—SO₂-(C₃₋₇)heterocycloalkyl. In a ninth embodiment, R^(g) representsoptionally substituted —SO₂-aryl. In a particular aspect of thatembodiment, R^(g) represents optionally substituted —SO₂-phenyl. In atenth embodiment, R^(g) represents optionally substituted—SO₂-heteroaryl. In a particular aspect of that embodiment, R^(g)represents optionally substituted —SO₂-pyridinyl. In an eleventhembodiment, R^(g) represents optionally substituted heteroaryl. In aparticular aspect of that embodiment, R^(g) represents optionallysubstituted pyrimidinyl. In a twelfth embodiment, R^(g) representsoptionally substituted (C₂₋₆)alkoxycarbonyl. In a particular aspect ofthat embodiment, R^(g) represents ethoxycarbonyl.

Illustrative values of R^(g) include hydrogen, methyl, carboxymethyl,ethoxycarbonylmethyl, methylcarbonyl, methylsulphonyl,(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)methylcarbonyl,azetidinylcarbonyl, (methylsulphonyl)azetidinylcarbonyl,pyridinylsulphonyl, cyclopropylsulphonyl,(tert-butyl)(dimethyl)silyloxyethyl, hydroxyethyl, phenylsulphonyl,(methoxy)pyridinylsulphonyl, (pyridine-2(1H)-one)sulphonyl, pyrimidinyland ethoxycarbonyl.

Selected values of R^(g) include hydrogen, methyl, carboxymethyl,ethoxycarbonylmethyl, methylcarbonyl, methylsulphonyl,(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)methylcarbonyl,azetidinylcarbonyl, (methylsulphonyl)azetidinylcarbonyl,pyridinylsulphonyl, cyclopropylsulphonyl,(tert-butyl)(dimethyl)silyloxyethyl, hydroxyethyl, phenylsulphonyl and(methoxy)pyridinylsulphonyl.

Particular values of R^(g) include hydrogen, methyl, carboxymethyl,ethoxycarbonylmethyl, methylcarbonyl and methylsulphonyl.

Specific values of R^(g) include hydrogen and methyl.

Illustrative values of —X-Q- include —O—, —O—CO—, —O—C(CH—CN)—, —S—,—SO—, SO₂—, —NH—, —N(CO—CH₃)—, —N(SO₂—CH₃)—, —N(CH₂—CO—O—CH₂—CH₃)—,—N[(CO—CH₂-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)]-,—N[CO-(azetidin-3-yl)]-, —N[CO-(methylsulphonyl)azetidin-3-yl)]-,—N(CH₂—COOH), —N[tert-butyl)(dimethyl)silyloxyethyl]-,—N(SO₂-pyridine-3-yl)-, —N—(SO₂-cyclopropyl)-, —N(CH₃)—CH₂—,—N(CH₂—CH₂—OH)—, —N(SO₂-phenyl)-, —N[SO₂-(6-methoxy-pyridin-3-yl)]-,—NH—CO—, —N(CH₃)—CO—, —N(CH₂CH₃)—CO—, —N(CH(CH₃)₂)—CO—,—N(CH₂—COOH)—CO—, —N(CH₂—CF₃)—CO—, —N(CH₂—CH₂—OH)—CO—,—N(CH₂—C(OH)(CH₃)₂)—CO—, —N(CD₃)—CO—, —NH—CH₂—N(CH₂—COOH)—CH₂—,—NH—CH(CF₃)—, —NH—CH(CH₃)—, —NH—C(S)—, —N(CO—CH₃)—CH(CH₃)—,—N(SO₂—CH₃)—CH₂—, —N(CO—CH₃)—CH(CH₃)—, —N═S(O)(CH₃)—, O—CH(CF₃)—,—CH(COOC₂H₅)—S—, —CH₂—S(O)—, —CH₂—S(O)₂—, —CH(CH(OH)(CH₃)₂)—S—,—CH(CH₂OH)—S—, —O—C(═CH₂)—, —N[S(O)₂-(pyridin-1H-2-one)], —NH—S(O)₂—,—N(pyrimidinyl)-, —N(COOC₂H₅)—, —S(═N—CN)—, —N(SO₂—CH₃)— and—N(C₂H₅)—CO—.

In a particular embodiment, the present invention provides a compound offormula (I) or an N-oxide thereof, or a pharmaceutically acceptable saltthereof:

wherein

X-Q- represents —O—, —O—C(O)—, —O—C(CH—CN)—, —S—, —SO-, or —SO₂—; or—N(R^(g))—, —N(R^(f))—CO—, —N(R^(f))—SO₂—, O—CH₂—, -, CH₂—S-, —CH₂—SO—,—CH₂—SO₂—, —N(R^(g))—CH₂—, —N(R^(f))—C(S)—, —N═S(O)(CH₃)—, —O—C(═CH₂)—or —S(═N—CN)—, any of which groups may be optionally substituted;

Z represents methylene;

E represents a fused heteroaromatic ring system selected from the groupsof formula (Ea) and (Eb);

wherein the asterisk (*) represents the site of attachment of E to theremainder of the molecule;

R¹ represents halogen or cyano; or aryl, heteroaryl,(C₃₋₇)cycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl-heteroaryl,(C₄₋₉)heterobicycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl ,(C₃₋₇)heterocycloalkenyl, or (C₃₋₇)heterocycloalkenyl-aryl, any of whichgroups may be optionally substituted by one or more substituents;

R² represents hydrogen or halogen;

R³ represents hydrogen or trifluoromethyl;

R⁴ represents hydrogen or trifluoromethyl;

R⁵ represents halogen, —OR^(a), difluoromethoxy or trifluoromethoxy;

R⁶ represents hydrogen, halogen or trifluoromethyl;

R⁷ represents hydrogen or trifluoromethyl;

R⁸ represents hydrogen, halogen or trifluoromethyl;

R¹² represents hydrogen or C₁₋₆ alkyl;

R^(a) represents C₁₋₆ alkyl;

R^(f) represents hydrogen; or C₁₋₆ alkyl, which group may be optionallysubstituted by one or more substituents; and

R^(g) represents hydrogen; or C₁₋₆ alkyl, —CO—(C₁₋₆)alkyl,—SO₂—(C₁₋₆)alkyl. —CO—(C₃₋₇)heterocycloalkyl, —SO₂-(C₃₋₇)cycloalkyl,—SO₂-aryl, —SO₂-heteroaryl, heteroaryl or (C₂₋₆)alkoxycarbonyl, any ofwhich groups may be optionally substituted by one or more substituents.

In a particular aspect of that embodiment, the present inventionprovides a compound of formula (I) or an N-oxide thereof, or apharmaceutically acceptable salt thereof,

X-Q- include —O—, —O—CO—, —O—C(CH—CN)—, —S—, —SO—, SO₂—, —NH—,—N(CO—CH₃)—, —N(SO₂—CH₃)—, —N(CH₂—CO—O—CH₂—CH₃)-,—N[(CO—CH₂-(3,7-dioxa-9-azabicyclo [3.3.1 ]non-9-yl)]-,—N[CO-(azetidin-3-yl)]-, —N[CO-(methylsulphonyl)azetidin-3-yl)]-,—N(CH₂—COOH), —N[(tert-butyl)(dimethyl)silyloxyethyl]-,—N(SO₂-pyridine-3-yl)-, —N—(SO₂-cyclopropyl)-, —N(CH₃)—CH₂—,—N(CH₂—CH₂—OH)—, —N(SO₂-phenyl)-, —N[SO₂-(6-methoxy-pyridin-3-yl)]-,—NH—CO—, —N(CH₃)—CO—, —N(CH₂CH₃)—CO—, —N(CH(CH₃)₂)—CO—,—N(CH₂—COOH)—CO—, —N(CH₂—CF₃)—CO—, —N(CH₂—CH₂—OH)—CO—,—N(CH₂—C(OH)(CH₃)₂)—CO—, —N(CD₃)—CO—, —NH—CH₂—, —N(CH₂—COOH)—CH₂—,—NH—CH(CF₃)—, —NH—CH(CH₃)—, —NH—C(S)—, —N(CO—CH₃)—CH(CH₃)—,—N(SO₂—CH₃)—CH₂—, —N(CO—CH₃)—CH(CH₃)—, —N═S(O)(CH₃)—, O—CH(CF₃)—,—CH(COOC₂H₅)—S—, —CH₂—S(O)—, —CH₂—S(O)₂—, —CH(CH(OH)(CH₃)₂)—S—,—CH(CH₂OH)—S—, —O—C(═CH₂)—, —N[S(O)₂-(pyridin-1H-2-one)], —NH—S(O)₂—,—N(pyrimidinyl)-, —N(COOC₂H₅)—, —S(═N—CN)—, —N(SO₂—CH₃)— and—N(C₂H₅)—CO—;

R¹ represents chloro, cyano, methylsulphonyl-phenyl,methylsulphoximinyl-phenyl, (dihydroxy)(methyl)cyclobutylpyrimidinyl,hydroxyisopropylpyridinyl, hydroxyisopropylpyrimidinyl,(methyl)(hydroxyisopropyl)pyrimidinyl, phosphate-isopropylpyrimidinyl,methoxypyridinyl, methoxyisopropylpyrimidinyl, 2-oxo-pyridin-(1H)-yl,(tert-butoxycarbonyl)aminoisopropyl-pyrimidinyl,aminoisopropylpyrimidinyl,(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-pyrimidinyl,(hydroxy)(trifluoromethyl)azetidinyl-pyrimidinyl,(methylsulphonyl)(methyl)phenyl, (methyl)(hydroxyisopropyl)pyridinyl,[(hydroxy)(trifluoromethyl)azetidinyl](methyl)pyrimidinylmethylsulphonylcyclopropylpyridinyl,(dimethyl)(hydroxyisopropyl)pyrimidinyl,(hydroxyisopropyl)(trifluoromethyl)pyrimidinyl,(tert-butoxycarbonyl)(hydroxy)pyrrolidine-pyridinyl,(hydroxy)pyrrolidine-pyridinyl,(methoxycarbonyl)aminoisopropyl-pyrimidinyl, piperazinylpyridinyl,(methylsulphonyl)piperazinyl-pyridinyl,(dimethylamino)isopropylpyrimidinyl, (oxo)piperazinylpyrimidinyl,(N-methyppyrazolyl, (methylthio)(methyl)phenyl, morpholinylpyrimidinyl,((tert-butyl)sulphinylamino)cyclobutylpyridinyl,(amino)cyclobutylpyridinyl,((tert-butyl)sulphinylamino)oxetanylpyridinyl, (amino)oxetanylpyridinyl,((tert-butyl)sulphonylamino)oxetanylpyridinyl, pyrrolidinylpyridinyl,(dimethyl)imidazolylphenyl, (methylsulphonyl)aminoisopropylpyrimidinyl,methylcarbonylaminoisopropylpyrimidinyl, pyrrolidinyl-phenyl,(oxo)diazepanylpyrimidinyl, (hydroxy)(methyl)azetidinyl-pyrimidinyl,thiomorpholinylpyrimidinyl, (oxo)thiomorpholinylpyrimidinyl,(dioxo)thiomorpholinylpyrimidinyl,(difluoro)(hydroxy)cyclohexylpyrimidinyl,(hydroxy)(oxo)tetrahydrothiophenyl-pyrimidinyl,(hydroxy)(dioxo)tetrahydrothiophenyl-pyrimidinyl,(hydroxy)tetrahydrothiophenyl-pyrimidinyl, (hydroxy)oxetanylpyrimidinyl,(methylsulphonyl)azetidinyl-2,5-pyrazolyl,(oxo)(methyl)-1,2-dihydropyridinyl, (oxo)-1,2-dihydropyrimidinyl,(dihydroxy)(methyl)cyclohexylpyrimidinyl, cyanoisopropylpyrimidinyl,(cyano)(methyl)azetidinylpyrimidinyl,(2-oxa-5-azabicyclo[2.2.1]heptanyl)-pyrimidinyl-,(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-pyrimidinyl-,(oxo)(3,6-diazabicyclo[3.2.2]nonanyl)-pyrimidinyl-,(hydroxyisopropyl)azetidinyl, (difluoro)azetidinylpyrimidinyl,tetrahydropyranylpyrimidinyl, methylsulphoxyminylpyridinyl,(difluoromethyl)(hydroxyisopropyl)pyrimidinyl,(tetrahydrofuranyl)(hydroxyisopropyl)pyrimidinyl,di(propenyl)aminoisopropylpyrimidinyl, sulphate-isopropylpyrimidinyl,carboxy-ethyl-carbonyloxy-isopropyl-pyrimidinyl and(hydroxy)isobutylpyrimidinyl;

R² represents hydrogen, bromo or fluoro;

R³ represents hydrogen or trifluoromethy;

R⁴ represents hydrogen or trifluoromethyl;

R⁵ represents halogen, methoxy, difluoromethoxy or trifluoromethoxy;

R⁶ represents hydrogen, bromo, chloro, or trifluoromethyl;

R⁷ represents hydrogen or trifluoromethyl;

R⁸ represents hydrogen, chloro and trifluoromethyl;

R¹² represents hydrogen or methyl;

R^(f) represents hydrogen, methyl, ethyl, isopropyl, (carboxy)methyl,(trifluoromethyl)methyl, (hydroxyisopropyl)methyl or deuterated methyl;

R^(g) represents hydrogen, methyl, carboxymethyl, ethoxycarbonylmethyl,methylcarbonyl, methylsulphonyl, (3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)methylcarbonyl, azetidinylcarbonyl,(methylsulphonyl)azetidinylcarbonyl, pyridinylsulphonyl,cyclopropylsulphonyl, (tert-butyl)(dimethyl)silyloxyethyl, hydroxyethyl,phenylsulphonyl, (methoxy)pyridinylsulphonyl,(pyridine-2(1H)-one)sulphonyl, pyrimidinyl or ethoxycarbonyl; and

Z and E are as defined in said particular embodiment.

A particular sub-group of the compounds of formula (IB) above isrepresented by the compounds of formula (IIB) and N-oxides thereof, andpharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R^(f) are as defined above.

A particular sub-group of compounds of formula (IIB) above isrepresented by the compounds of formula (IIB-A) and N-oxides thereof,and pharmaceutically acceptable salts thereof:

wherein wherein R¹, R², R⁵ and R^(f) are as defined above.

A particular sub-group of compounds of formula (IIB-A) above isrepresented by the compounds of formula (IIB-AB) and N-oxides thereof,and pharmaceutically acceptable salts thereof:

wherein,

W represents N or C-H;

R⁹ represents hydroxy(C₁₋₆)alkyl, (C₁₋₆) alkoxy(C₁₋₆)alkyl,amino(C₁₋₆)alkyl or phosphate(C₁₋₆)alkyl;

R¹⁰ represents hydrogen or C₁₋₆ alkyl; and

R², R⁵ and R^(f) are as defined above.

In one embodiment, W represents N. In another embodiment, W representsC—H.

Suitably, R⁹ represents hydroxy(C₁₋₆)alkyl or (C₁₋₆)alkoxy(C₁₋₆)alkyl.

Illustratively, R⁹ represents hydroxyisopropyl or methoxyisopropyl.

Particular values of R⁹ include 2-hydroxy-prop-2-yl and2-methoxy-prop-2-yl.

In one embodiment, R⁹ represents hydroxyisopropyl. In a particularaspect of that embodiment, R⁹ represents 2-hydroxy-prop-2-yl.

In another embodiment, R⁹ represents methoxyisopropyl. In a particularaspect of that embodiment, R⁹ represents 2-methoxy-prop-2-yl.

In a further embodiment, R⁹ represents aminoisopropyl. In a particularaspect of that embodiment, R⁹ represents 2-amino-prop-2-yl.

In another embodiment, R⁹ represents phosphate(C₁₋₆)alkyl. In aparticular aspect of that embodiment, R⁹ represents2-phosphate-prop-2-yl.

In one embodiment, R¹⁰ represents hydrogen. In another embodiment, R¹⁰represents C₁₋₆ alkyl. In a particular aspect of this embodiment, R¹⁰represents methyl.

Illustratively, R¹⁰ represents hydrogen or methyl.

Particularly, R¹⁰ represents hydrogen.

A particular sub-group of compounds of formula (IIB-AB) above isrepresented by the compounds of formula (IIB-AB-A) and N-oxides thereof,and pharmaceutically acceptable salts thereof:

wherein W, R^(f), R², R⁵ , R⁹ and R¹⁰ are as defined above.

Another particular sub-group of the compounds of formula (IB) above isrepresented by the compounds of formula (IIC) and N-oxides thereof, andpharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R^(g) are as defined above.

Specific novel compounds in accordance with the present inventioninclude each of the compounds whose preparation is described in theaccompanying Examples, and pharmaceutically acceptable salts andsolvates thereof, and co-crystals thereof.

Therefore, in a particular aspect, the present invention relates tocompounds of formula (I) which are selected from the group consisting of(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-methoxypropan-2-yl)pyrimidin-5-yl]-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-6-ethyl-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-(propan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-5(14H)-one;(2Z)-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-5(14H)-ylidene]acetonitrile;(2E)-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-5(14H)-ylidene]acetonitrile;(7R,14R) and (7S,14S)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7,14-dihydro-7,14-methanopyrido[1′,2′:1,2]imidazo[4,5-d][2]benzazocin-5(6H)-one;(7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-11-chloro-1-(difluoromethoxy)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazoeine;[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]aceticacid;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazoeine-5 (14H)-thione;(7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazoeine;2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;(7R,14R)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-1-methoxy-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1,10-difluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(6R,12R)-2-chloro-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine;2-{5-[(6R,12R)-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;1-[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]ethanone;1-[(6R,12R)-11-(difluoromethoxy)-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]ethanone;(6R,12R)-2-chloro-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine;2-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;(6R,12R)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzoxazepine;2-{5-[(6R,12R)-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzoxazepin-2-yl]pyrimidin-2-yl}propan-2-ol;(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine-11-carbonitrile;(7R,14R)-1-(difluoromethoxy)-11-[4-(methylsulfonyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14M-one;(7R,14R)-1-(difluoromethoxy)-11-(6-methoxypyridin-3-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one;(7R,14R)-1-(difluoromethoxy)-11-(6-oxo-1,6-dihydropyridin-3-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14M-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)-6-methyl-pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-6-methyl-pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one;(7R,14R)-1-(difluoromethoxy)-11-[4-(S-methylsulfonimidoyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one; (1R,11R)-18-(difluoromethoxy)-6-fluoro-5-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-3,9,12-triazapentacyclo[9.8.1.0²,¹ ⁰ .0³,⁸.0¹ ⁴ , ¹ ⁹ ]icosa-2(10),4,6,8,14(19),15,17-heptaen-13-one hydrochloride;(7R,14R)-1-(difluoromethoxy)-11-[2-(cis-1,3-dihydroxy-3-methylcyclobutyl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one; ethyl[(6R,12R)-11-(difluoromethoxy)-3-fluoro-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]acetate;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; tert-butyl(2-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-yl)carbamate;2-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-amine;azetidin-3-yl[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]methanone;[(6R,12R)-11-(difluoromethoxy)-3-fluoro-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl][1-(methylsulfonyl)azetidin-3-yl]methanone;2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;azetidin-3-yl[6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]methanone;cis-1-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}-3-methylcyclobutane-1,3-diol;(6R,12R)-11-(difluoromethoxy)-2-{2-[(1s ,5s)-3 ,7-dioxa-9-azabicyclo[3.3.1]non-9-yl]pyrimidin-5-yl}-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine;[(6R,12R)-11-(difluoromethoxy)-3-fluoro-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]aceticacid;2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(pyridin-3-ylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;1-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}-3-(trifluoromethyl)azetidin-3-ol;2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(6R,12R)-7-(cyclopropylsulfonyl)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(6R,12R)-7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(2-hydroxyethyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(phenylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;2-(5-{(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-[(6-methoxypyridin-3-yl)sulfonyl]-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl}pyrimidin-2-yl)propan-2-ol;2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(phenylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;2-(5-{(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-[(6-methoxypyridin-3-yl)sulfonyl]-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl}pyrimidin-2-yl)propan-2-ol;[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-oxo-5,14-dihydro-7,14-methanobenzimidazo [1,2-b][2,5]benzodiazocin-6(7M-yl]acetic acid;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-(2,2,2-trifluoroethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one;(7R,14R)-1-(difluoromethoxy)-6-(2-hydroxyethyl)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one;(7R,14R)-1-(difluoromethoxy)-6-(2-hydroxy-2-methylpropyl)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14M-one;(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-(trideutero)methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one;(7R,14R)-1-(difluoromethoxy)-11-{6-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyridin-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14M-one; (6R,12R)-3 ,10-dibromo-2-chloro-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine;(6R,12R)-2,8,10-trichloro-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4-methylpyrimidin-5-yl]-7,14-dihydro-7,14-methanopyrido[1′,2′: 1,2]imidazo[4,5-d][2]b enzazocin-5 (6M-one;(7R,14R)-1-(difluoromethoxy)-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-{2-[3-hydroxy-3-(trifluoromethypazetidin-1-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(141)-one;(7R,14R)-1-(difluoromethoxy)-11-{2-[(1s ,5s)-3,7-dioxa-9-azabicyclo [3.3.1]non-9-yl]pyrimidin-5-yl}-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)one;(7R,14R)-1-(difluoromethoxy)-11-[2-methyl-4-(methylsulfonyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(141)-one;(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;2-{5-[(7R,14R)-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol ; 2-{5-[(5R or 5S,7R,14R)-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol ; 2-{5-[(5R or 5S,7R,14R)-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol ;1-[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone;1-[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone;2-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo [1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-(methylsulfonyl)-5 ,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo [1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(5S,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5 ,6,7,14-tetrahydro-7,14-methanobenzimidazo [1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol; 2-{5-[(5S ,7 R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo [1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-1-oxidopyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-{6-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-2-methylpyridin-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(141)-one;(6R,12R)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine;2-{5-[(6R,12R)-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;(6R,7R,12S)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine7-oxide;(6R,7S,12S)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine 7-oxide;2-{5-[(6R,7R,12S)-11-(difluoromethoxy)-7-oxido-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(6R,7S,12S)-11-(difluoromethoxy)-7-oxido-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;(6R,12R)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine7,7-dioxide;2-{5-[(6R,12R)-11-(difluoromethoxy)-7,7-dioxido-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol;1-[(5R,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone;1-[(5S,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone;1-[(5R,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone;1-[5S,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone;(7R,14R)-10-fluoro-1-hydroxy-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one;2-{5-[(7R,14R)-1-(difluoromethoxy)-5-methyl-5-oxido-7,14-dihydro-7,14-methano -5 k-4-benzimidazo [2,1-d][1,2,5]benzothiadiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;(7R,14R)-1-(difluoromethoxy)-11-{6-[1-(methylsulfonyl)cyclopropyl]pyridin-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4,6-dimethylpyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,14-dihydro-7H-7,14-methanobenzimidazo [2,1-d][2,5]benzoxazocin-11-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(5S,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,14-dihydro-7H-7,14-methanobenzimidazo [2,1-d][2,5]benzoxazocin-11-yl]pyrimidin-2-yl}propan-2-ol;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-12-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-4-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-9-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-3-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14M-one;2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanopyrido[1′,2′: 1,2]imidazo[4,5-c][1]benzazepin-2-yl]pyrimidin-2-yl}propan-2-ol;(7R,14R)-1-(difluoromethoxy)-11-[2-(cis-1,3-dihydroxy-3-methylcyclobutyl)pyrimidin-5-yl]-6-trideutero-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one; Ethyl(7R,14S)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate; ethyl(7R,14S)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate;2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-oxido-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(7R,14R)-1-(difluoromethoxy)-5,5-dioxido-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

2-{5-[(6R,7R,14S)-1-(difluoromethoxy)-6-(2-hydroxypropan-2-yl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-01;2-{5-[(6S,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;2-{5-[(6R,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one;(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)-1-oxidopyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14M-one;(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)-1-oxidopyridin-3-yl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;2-{5-[(6R,12R)-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-amine,dihydrochloride salt; tert-Butyl3-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}-3-hydroxypyrrolidine-1-carboxylate;(7R,14R)-1-(difluoromethoxy)-11-[6-(3-hydroxypyrrolidin-3-yl)pyridin-3-yl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one, dihydrochloride salt; methyl(2-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo [1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)-4-methylpyrimidin-5-yl]-6-trideutero-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-11-chloro-1-(difluoromethoxy)-5-methylidene-5,14-dihydro-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazoeine;(7R,14R)-1-(difluoromethoxy)-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyrimidin-5-yl}-6-trideutero-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[6-(piperazin-1-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-6-trideutero-methyl-11-[6-(piperazin-1-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-6-trideutero-methyl-11-[6-[4-(methylsulfonyl)piperazin-1yl)pyridine-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; (7R,14R)-1-(difluoromethoxy)-11-{2--82-(dimethylamino)propan-2-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;1-[(6R,12R)-11-(difluoromethoxy)-2-(1-methyl-1H-pyrazol-4-yl)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]-2-(3,7-dioxa-9-azabicyclo [3 .3.1]non-9-yl)ethanone;(6R,12R)-2-chloro-11-(difluoromethoxy)-7-[(6-methoxypyridin-3-yl)sulfonyl]-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine;5-{[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]sulfonyl}pyridin-2(11)-one;2-{5-[(7R,14R)-1-(difluoromethoxy)-5,5-dioxido-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,2,5]benzothiadiazocin-11-yl]pyrimidin-2-yl}propan-2-ol;(7R,14R)-1-(difluoromethoxy)-11-[2-methyl-4-(methylsulfanyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(morpho lin-4-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(6R,12R)-2-chloro-11-(difluoromethoxy)-7-(pyrimidin-2-yl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine;ethyl-(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine-7(12H)-carboxylate;ethyl-(6R,12R)-11-(difluoromethoxy)-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine-7(12H)-carboxylate;N-(1-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}cyclobutyl)-2-methylpropane-2-sulfinamide;(7R,14R)-11-[6-(1-aminocyclobutyppyridin-3-yl]-1-(difluoromethoxy)-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;N-(3-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfinamide;(7R,14R)-11-[6-(3-aminooxetan-3-yl)pyridin-3-yl]-1-(difluoromethoxy)-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;N-(3-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfinamide;N-(3-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-11-yl]-1-oxidopyridin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfonamide;(7R,14R)-1-(difluoromethoxy)-11-[4-(2,4-dimethyl-1H-imidazo1-5-yl)phenyl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[4-(2,4-dimethyl-1H-imidazol-5-yl)phenyl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[4-(2,4-dimethyl-1H-imidazol-5-yl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1 ,2-b][2,5 ]benzodiazocin-5 (14H)-one;[(6R,7E,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methano-7k-4-benzimidazo[2,1-c][1,4]benzothiazepin-7(12H)-ylidene]cyanamide;N-(2-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)methanesulfo namide;N-(2-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)ac etamide;(7R,14R)-1-(difluoromethoxy)-11-[4-(pyrrolidin-2-yl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-6-trideutero-methyl-11-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-6-methyl-11-[2-(5-oxo-1,4-diazepan-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-5(14H)-one;(7R,14R)-11-[4-(2-aminopropan-2-yl)phenyl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(3-hydroxy-3-methylazetidin-1-yl)-4-methylpyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-trideutero-methyl-11-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(1-oxidothiomorpholin-4-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-11-[2-(4,4-difluoro-1-hydroxycyclohexyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(3-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(3R)-3-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-3-hydroxytetrahydrothiophenium-1-olate;(3S)-3-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-3-hydroxytetrahydrothiophenium-1-olate;(7R,14R)-1-(difluoromethoxy)-11-[2-(3-hydroxyoxetan-3-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-{1-[1-(methylsulfonyl)azetidin-3-yl]-1H-pyrazol-4-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-(2-hydroxypyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(1,4-dihydroxy-4-methylcyclohexyl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one; 2-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-2-methylpropanenitrile;1-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-3-methylazetidine-3-carbonitrile ;(7R,14R)-1-(difluoromethoxy)-11-{2-[(1 S,4 S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(thiomorpholin-4-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-{2-[3-(2-hydroxypropan-2-yl)azetidin-1-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one; (7R,14R)-11-[2-(3,3-difluoroazetidin-1-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(3-oxa-8-azabicyclo [3 .2 .1]oct-8-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(7-oxo-3 ,6-diazabicyc lo [3 .2.2]non-3-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(1,1-dioxidothiomorpholin-4-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6,7-dihydro-7,14-methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-10-fluoro-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-1-(trifluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-11-((2-aminopropan-2-yl)phenyl)-10-fluoro-1-(trifluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-11-((2-aminopropan-2-yl)phenyl)-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1 ,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4-(tetrahydrofuran-3-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[4-(difluoromethyl)-2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-6-ethyl-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one;(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-6-ethyl-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one ; (7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one ; (7R,14R)-1-(difluoromethoxy)-11-(2-{2-[di(prop-2-en-1-yl)amino]propan-2-yl}pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one ; (7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-11-[6-(S-methylsulfonimidoyl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[6-(S-methylsulfonimidoyl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5 (14H)-one ; (7R,14R)-1-(difluoromethoxy)-11-(2-{2-[di(prop-2-en-1-yl)amino]propan-2-yl}pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one;(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-(2-((2R*)-hydroxybutan-2-yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo [4 ,5 ]imidazo[1,2-a][1,4]diazocin-5 (14H)-one ; (7R,14R)-1-(difluoromethoxy)-10-fluoro-11-(2-((2S*)-hydroxybutan-2-yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo [4 ,5 ]imidazo[1,2-a][1,4]diazocin-5 (14H)-one ;2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl phosphate,disodium salt;2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2 ,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl phosphate, disodiumsalt; ammonium 2-(5-((7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo [f]benzo [4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)propan-2-yl sulphate;and 4-((2-(5-((7R ,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo [f]benzo [4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)propan-2-yl)oxy)-4-oxobutanoic acid.

The compounds in accordance with the present invention are beneficial inthe treatment and/or prevention of various human ailments. These includeautoimmune and inflammatory disorders; neurological andneurodegenerative disorders; pain and nociceptive disorders;cardiovascular disorders; metabolic disorders; ocular disorders; andoncological disorders.

Inflammatory and autoimmune disorders include systemic autoimmunedisorders, autoimmune endocrine disorders and organ-specific autoimmunedisorders. Systemic autoimmune disorders include systemic lupuserythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis,inflammatory myopathy (including polymyositis, dermatomyositis,inclusion body myositis), scleroderma, multiple sclerosis, systemicsclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specificinflammatory arthritis, juvenile inflammatory arthritis, juvenileidiopathic arthritis (including oligoarticular and polyarticular formsthereof), anaemia of chronic disease (ACD), Still's disease (juvenileand/or adult onset), Behcet's disease and Sjogren's syndrome. Autoimmuneendocrine disorders include thyroiditis. Organ-specific autoimmunedisorders include Addison's disease, haemolytic or pernicious anaemia,acute kidney injury (AKI; including cisplatin-induced AKI), diabeticnephropathy (DN), obstructive uropathy (including cisplatin-inducedobstructive uropathy), glomerulonephritis (including Goodpasture'ssyndrome, immune complex-mediated glomerulonephritis and antineutrophilcytoplasmic antibodies (ANCA)-associated glomerulonephritis), lupusnephritis (LN), minimal change disease, Graves' disease, idiopathicthrombocytopenic purpura, inflammatory bowel disease (including Crohn'sdisease, ulcerative colitis, indeterminate colitis and pouchitis),pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliarycirrhosis, autoimmune pneumonitis, autoimmune carditis, myastheniagravis, spontaneous infertility, osteoporosis, osteopenia, erosive bonedisease, chondritis, cartilage degeneration and/or destruction,fibrosing disorders (including various forms of hepatic and pulmonaryfibrosis), asthma, rhinitis, chronic obstructive pulmonary disease(COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy(including Duchenne muscular dystrophy) and organ transplant rejection(including kidney allograft rejection).

Additional inflammatory and autoimmune disorders includescleritis,Takayasu arteritis, giant cell arteritis scleritis,hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgiarheumatica, axial spondylo arthritis. Neurological and neurodegenerativedisorders include Alzheimer's disease, Parkinson's disease, Huntington'sdisease, ischaemia, stroke, amyotrophic lateral sclerosis, spinal cordinjury, head trauma, seizures and epilepsy.

Cardiovascular disorders include thrombosis, cardiac hypertrophy,hypertension, irregular contractility of the heart (e.g. during heartfailure), and sexual disorders (including erectile dysfunction andfemale sexual dysfunction). Modulators of TNFα function may also be ofuse in the treatment and/or prevention of myocardial infarction (see J.J. Wu et al., JAMA, 2013, 309, 2043-2044).

Metabolic disorders include diabetes (including insulin-dependentdiabetes mellitus and juvenile diabetes), dyslipidemia and metabolicsyndrome.

Ocular disorders include retinopathy (including diabetic retinopathy,proliferative retinopathy, non-proliferative retinopathy and retinopathyof prematurity), macular oedema (including diabetic macular oedema),age-related macular degeneration (ARMD), vascularisation (includingcorneal vascularisation and neovascularisation), retinal vein occlusion,and various forms of uveitis (including iritis) and keratitis

Oncological disorders, which may be acute or chronic, includeproliferative disorders, especially cancer, and cancer-associatedcomplications (including skeletal complications, cachexia and anaemia).Particular categories of cancer include haematological malignancy(including leukaemia and lymphoma) and non-haematological malignancy(including solid tumour cancer, sarcoma, meningioma, glioblastomamultiforme, neuroblastoma, melanoma, gastric carcinoma and renal cellcarcinoma). Chronic leukaemia may be myeloid or lymphoid. Varieties ofleukaemia include lymphoblastic T cell leukaemia, chronic myelogenousleukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL),hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acutemyelogenous leukaemia (AML), myelodysplastic syndrome, chronicneutrophilic leukaemia, acute lymphoblastic T cell leukaemia,plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia,multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocyticleukaemia, promyelocytic leukaemia and erythroleukaemia. Varieties oflymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin'slymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicularlymphoma, MALT1 lymphoma and marginal zone lymphoma. Varieties ofnon-haematological malignancy include cancer of the prostate, lung,breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver,ovary, uterus, cervix, brain, skin, bone, stomach and muscle. Modulatorsof TNFα function may also be used to increase the safety of the potentanticancer effect of TNF (see F. V. Hauwermeiren et al., J. Clin.Invest., 2013, 123, 2590-2603).

Compounds according to the present invention can be particularlybeneficial for the treatment of rheumatoid arthritis, psoriasis,psoriatic arthropathy, axial spondyloarthritis, juvenile idiopathicarthritis, Crohn's disease, ulcerative colitis, uveitis, Behcet'sdisease and Takayasu arteritis.

The present invention also provides a pharmaceutical composition whichcomprises a compound in accordance with the invention as describedabove, or a pharmaceutically acceptable salt or solvate thereof, inassociation with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical, ophthalmic orrectal administration, or a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methyl cellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogenphosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles or preservatives. Thepreparations may also contain buffer salts, flavouring agents, colouringagents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteraladministration by injection, e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoules or multi-dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (I) may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation for pressurised packs or anebuliser, with the use of a suitable propellant, e.g.dichlorodifluoromethane, fluorotrichloromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

For topical administration the compounds of use in the present inventionmay be conveniently formulated in a suitable ointment containing theactive component suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Particular carriers include, for example, mineraloil, liquid petroleum, propylene glycol, polyoxyethylene,polyoxypropylene, emulsifying wax and water. Alternatively, thecompounds of use in the present invention may be formulated in asuitable lotion containing the active component suspended or dissolvedin one or more pharmaceutically acceptable carriers. Particular carriersinclude, for example, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanoland water.

For ophthalmic administration the compounds of use in the presentinvention may be conveniently formulated as micronized suspensions inisotonic, pH-adjusted sterile saline, either with or without apreservative such as a bactericidal or fungicidal agent, for examplephenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively, for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration the compounds of use in the present inventionmay be conveniently formulated as suppositories. These can be preparedby mixing the active component with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andso will melt in the rectum to release the active component. Suchmaterials include, for example, cocoa butter, beeswax and polyethyleneglycols.

The quantity of a compound of use in the invention required for theprophylaxis or treatment of a particular condition will vary dependingon the compound chosen and the condition of the patient to be treated.In general, however, daily dosages may range from around 10 ng/kg to1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01mg/kg to 40 mg/kg body weight, for oral or buccal administration, fromaround 10 ng/kg to 50 mg/kg body weight for parenteral administration,and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg toaround 1000 mg, for nasal administration or administration by inhalationor insufflation.

If desired, a compound in accordance with the present invention may beco-administered with another pharmaceutically active agent, e.g. ananti-inflammatory molecule.

It will be apparent to the person skilled in the art that there arevarious synthetic pathways that can lead to the compounds according tothe invention. The following processes are aimed at illustrating some ofthese synthetic pathways but should not be construed in any way as alimitation on how the compounds according to the invention should bemade.

It will also be apparent to the person skilled in the art that there maybe variations in the synthetic pathways depending on the sub-classes ofcompounds of formula (I).

Compounds of formula (I) above, may be prepared by a process whichcomprises intramolecular cyclisation or includes reaction of anintermediate of formula (III),

wherein E, Z, R⁵, R⁶, R⁷,R⁸ and R¹² are as defined above;

X¹ represents hydroxy, —SH, CH₂—OH, —CO₂H, —NHR^(f), —NHRg,—C(O)—NHR^(f), Y, or —CH₂—Y;

Q¹ represents hydrogen, hydroxy, halogen, amino, —SR^(i), —CO₂H, —CH₂—Y,—CO—R^(j) or —CH(OH)—CF₃

Y represents a suitable leaving group;

R^(f) and R^(g) are as defined above,

R^(i) represents hydrogen, methyl, —CH—C(O)—O—C₂H₅, or—(CH₂)₂—C(O)—O—CH₂—CH (CH₂CH₃) [(CH₂)₃CH₃]; and

R^(j) represents hydrogen or methyl.

Suitably, Y represents halogen or (C₁₋₆)alkylsulphonate.

Appositely, Y represents bromo or methylsulphonate.

Suitably, R^(f) and R^(g) represent hydrogen.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —O— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ represents a leaving group Y, e.g. halogen,preferably bromo, and Q¹ represents hydroxy, in the presence of a base,for example sodium hydride or silver carbonate.

Alternatively, compounds of formula (I) wherein R¹² represents hydrogenand —X-Q- represents —O— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ represents hydroxy and Q¹ represents aleaving group Y, e.g. halogen, preferably bromo, in the presence of abase, e.g. an inorganic base such as cesium carbonate, and copperiodide, at elevated temperature.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —O—C(CH—CN)— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ represents hydroxy and Q¹ represents —CO₂H,in the presence of cyanomethylenetributylphosphorane.

Such intramolecular cyclization is conveniently performed at elevatedtemperature in a suitable solvent, e.g., toluene.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —O—C(O)— may be prepared by the same process as describedabove for compounds of formula (I) wherein R¹² represents hydrogen and—X-Q- represents —O—C(CH—CN)—, followed by treatment with a base, e.g.,potassium hydroxide.

Alternatively, compounds of formula (I) wherein R¹² represents hydrogenand —X-Q- represents —O—C(O)— may be prepared prepared by a processwhich comprises intramolecular cyclization of an intermediate of formula(III) wherein R¹² represents hydrogen, X¹ represents hydroxy and Q¹represents —CO₂H, in the presence of an acid, e.g. a mineral acid, in asuitable solvent.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —C(O)—O— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ represents —CO₂H and Q¹ represents —OH, inthe presence of thionyl chloride, or alternatively, by using a suitablecoupling reagent, according to methods known to the person skilled inthe art.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —S—, may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinX¹ represents —SH and Q¹ represents halogen, in the presence of atransition metal catalyst, according to a method analogous to thatdescribed in Stambuli J. et al, J. Org. Chem., 2009, 74, 4005-4008.

Alternatively, compounds of formula (I) wherein R¹² represents hydrogenand —X-Q- represents —S—, may be prepared by a process which comprisesreacting an intermediate of formula (III) wherein R¹² representshydrogen, X¹ represents —OH and Q¹ represents —S—(CH₂)₂—C(O)—O—CH₂—CH(CH₂CH₃) [(CH₂)₃CH_(3],) with methanesulphonylchloride in the presenceof a base, e.g. N,N-diisopropylethylamine, in a suitable solvent, e.g.tetrahydrofuran, to afford the corresponding compound wherein X¹represents a mesylate moity, followed by reaction with a solution ofsodium ethoxide.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —N(R^(g))—, may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ represents —NHR^(g) and Q¹ representshalogen, in the presence of a suitable transition metal catalyst,according to methods known to the person skilled in the art.

The intramolecular cyclization may be conveniently effected in thepresence of palladium(II)acetate and(+/−)-2,2′-bis(diphenylphosphino)1,1′-binaphthyl, in the presence ofbase, e.g., potassium carbonate or cesium carbonate, in a suitablesolvent, e.g., toluene, at elevated temperature.

Alternatively, compounds of formula (I) wherein R¹² represents hydrogenand —X-Q- represents —N(R^(g))-, and R^(g) represents hydrogen, may beprepared by a process which comprises intramolecular cyclization of anintermediate of formula (III) wherein R¹² represents hydrogen, X¹ is aleaving group Y, e.g. methylsulphonate, and Q¹ represents amino. Thereaction is conveniently effected by first protecting the amino group ofQ¹ with a suitable protecting group, e.g. tert-butoxy carbonyl,according to methods known to the person skilled in the art, followed bysubsequent addition of a suitable base, e.g. sodium hydride in asuitable solvent, e.g. dimethyl formamide.

Alternatively, compounds of formula (I) wherein R¹² represents hydrogen,—X-Q- represents —N(R^(g))—, and R^(g) represents—OC—(C₃₋₇)heterocycloalkyl, may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ represents —NHR^(g), wherein R^(g) is asdefined above, and Q¹ represents halogen. The reaction is convenientlyeffected by addition of a suitable base, e.g. cesium acetate, andcuprous iodide in a suitable solvent, e.g. dimethylsulfoxide, atelevated temperature. Compounds of formula (I) wherein R¹² representshydrogen, —X-Q- represents —N(R^(g))-, and R^(g) represents respectively(C₂₋₆)alkoxycarbonyl, heteroaryl-SO₂-heteroaryl or —SO₂-aryl may beprepared via an analogous method to the one described here above forR^(g) representing —CO—(C₃₋₇)heterocycloalkyl.

Compounds of formula (I) wherein R¹² represents hydrogen or methyl,—X-Q- represents —N(R^(f))—C(O)—, may be prepared by a process whichcomprises intramolecular cyclization of an intermediate of formula (III)wherein R¹² represents hydrogen or methyl, X¹ represents —NHR^(f) and Q¹is halogen, preferably chloro, in the presence of carbon monoxide and atransition metal catalyst.

The reaction is conveniently carried out at elevated temperature, e.g.100° C. or 150° C., and under an elevated pressure of carbon monoxide,in a suitable sovent solvent, e.g., a cyclic ether such as 1,4-dioxane,or dimethylsulfoxide or dimethylacetamide

The transition metal catalyst of use in the above reaction is suitablyselected from dichloro [bis(dicyclohexylphosphino)propane]palladium(II),[bis(diphenylphosphino)xanthene]palladium(II) and2,2-dichloro-1,1,3,3-tetracyclohexyl-1λ⁵, 3λ⁵ palladacyclohexane.

Alternatively, a solution of palladium (II) acetate and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in a suitable solventmay be used.

An analogous reaction may be performed using molybdenum hexacarbonyl asan alternative source of carbon monoxide.

Such intramolecular cyclization is conveniently performed in thepresence of a base, e.g. an inorganic base such as sodium carbonate orby activation using molecular sieves.

Alternatively, compounds of formula (I) wherein, —X-Q- represents—N(R^(f))—C(O)—, may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) wherein,X¹ represents —NHR^(f) , R^(f) represents hydrogen, and Q¹ is —COOH, inthe presence of 4-methylmorpholine and(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholinocarbenium hexafluorophosphate (COMU). Thereaction is conveniently effected in acetonitrile.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —C(O)—N(R^(f))— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen , X¹ is —C(O)—NH(R^(f)) and Q¹ is halogen,preferably bromine, in the presence of a suitable coupling reagent,according to methods known to the person skilled in the art.

Alternatively, compounds of formula (I) wherein R¹² represents hydrogen,—X-Q- represents —C(O)—N(R^(f))—, and R^(f) represents hydrogen, may beprepared by a process which comprises intramolecular cyclization of anintermediate of formula (III) wherein R¹² represents hydrogen, X¹represents —CO₂H and Q¹ represents amino. The reaction may beconveniently effected with a suitable coupling agent, e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), according tomethods known to the person skilled in the art.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —N(R^(f))—SO₂— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ represents —NHR^(f) and Q¹ represents —SH,in the presence of hydrogen peroxide and thionyl chloride according to amethod analogous to that described by K. Bahrami, M. M. Khodaei, M.Soheilizad, J. Org. Chem., 2009, 74, 9287-9291.

The reaction is conveniently performed at room temperature in a suitablesolvent, e.g. an apolar solvent such as acetonitrile and in the presenceof an organic base, e.g. pyridine.

Compounds of formula (I) wherein R¹² represents hydrogen, —X-Q-represents —SO₂—N(R^(f))—, and R^(f) represents hydrogen, may beprepared by a process analogous to the one described above for —X-Q-which represents —N(R^(f))—SO₂—, from an intermediate of formula (III)wherein R¹² represents hydrogen, X¹ represents —SH and Q¹ representsamino. The reaction is conveniently effected by first protecting theamino group of Q¹ with a suitable protecting group according to methodsknown to the person skilled in the art.

Compounds of formula (I) wherein R¹² represents hydrogen, —X-Q-represents —CH₂—CH₂— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen , X¹ represents —CH₂—CO₂H and Q¹ representshydrogen, for example applying Friedel Crafts reaction conditions, inthe presence of polyphosphoric acid. The resulting intermediate, wherein—X-Q- represents —CH₂—C(O)— is subsequently reduced according to methodsknown to the person skilled in the art.

Compounds of formula (I) wherein —X-Q- represents R¹² representshydrogen and —O—CH₂— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ represents hydroxy and Q¹ represents —CH₂—Y,wherein Y is a leaving group, e.g. halogen, preferably bromo, in therepresence of a suitable base, according to methods known to the personskilled in the art.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —CH₂—O— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ represents —CH₂—OH and Q¹ representshalogen, preferably bromo. This reaction is conveniently effected in thepresence of a suitable transition metal catalyst, e.g. palladium (II) orcopper (II) catalyst, according to methods known to the person skilledin the art.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —S—CH₂ may be prepared by a process analogous to the processof preparation of compounds of formula (I) wherein —X-Q- represents—O—CH₂— starting from intermediates of formula (III) wherein R¹²represents hydrogen, X¹ represents —SH and Q¹ represents —CH₂-Y.

Compounds of formula (I) wherein R¹² represents hydrogen and —X-Q-represents —CH₂—S— may be prepared by a process which comprisesintramolecular cyclization of an intermediate of formula (III) whereinR¹² represents hydrogen, X¹ is —CH₂—Y, Y is a suitable leaving group,e.g. halogen, and Q¹ represents —SH, in the presence of suitable baseaccording to methods known to the person skilled in the art.

Compounds of formula (I) wherein R¹² represents hydrogen , —X-Q-represents —CH₂—N(R^(g))—, and R^(g) represents hydrogen, may beprepared by a process which comprises intramolecular cyclization of anintermediate of formula (III) wherein R¹² represents hydrogen , X¹ is—CH₂—Y, wherein Y is a suitable leaving group, e.g. methylsulphonate,and Q¹ represents amino. The reaction is conveniently effected by firstprotecting the amino group of Q¹ with a suitable protecting group, e.g.tert-butoxy carbonyl, according to methods known to the person skilledin the art, followed by subsequent addition of a suitable base, e.g.sodium hydride in a suitable solvent, e.g. dimethyl formamide.

Compounds of formula (I) wherein R¹² represents hydrogen, —X-Q-represents —N(R^(g))—CH₂— and R^(g) represents hydrogen may be preparedby a process involving intramolecular cyclization of the correspondingcompound of formula (III) wherein R¹² represents hydrogen, X¹ represents—NH(R^(g)) and wherein Q¹ represents formyl. The reaction isconveniently effected by (i) reaction with an acid, e.g. trifluoroaceticacid, in a suitable solvent, e.g. dichloromethane and (ii) reduction ofthe compound obtained as a result of step (i) with an appropriatereducing agent, e.g. polymer supported cyano borohydride orborane-dimethylsulphide complex, in a suitable solvent, e.g.tetrahydrofuran or a mixture of tetrahydrofuran and ethanol.

Compounds of formula (I) wherein R¹² represents hydrogen, —X-Q-represents —N(R^(g))—CH(CH₃)— and R^(g) represents hydrogen may beprepared according to a method analogous as the one described here abovefor compounds of formula (I) wherein —X-Q- represents —N(R^(g))—CH₂—,but from intermediate of formula (III) wherein Q¹ represents acetyl.

Compounds of formula (I) wherein R¹² represents hydrogen, —X-Q-represents —N(R^(g))—CH(CF₃)— and R^(g) represents hydrogen may beprepared according to a method analogous to the one described here abovefor compounds of formula (I) wherein R12 represents hydrogen and —X-Q-represents —N(R^(g))—CH₂—, by reacting compound obtained as a result ofstep (i) with (trifluoromethyl)trimethyl silane, in the presence oftrifluoroacetic acid and potassium hydrogen fluoride, in a suitablesolvent, e.g. dimethylformamide.

Compounds of formula (I) wherein R¹² represents hydrogen, —X-Q-represents —N═S(O)(CH₃)— may be prepared by a process involvingintramolecular cyclization of the corresponding compound of formula(III) wherein, X¹ represents —NH(R^(g)), R^(g) represents hydrogen, andwherein Q¹ represents —SCH₃. The reaction is conveniently effected by(i) adding bromine in dichloromethane followed by (ii) oxidation e.g.with m-chloroperbenzoic acid.

Compounds of formula (I) wherein R¹² represents hydrogen, —X-Q-represents —O—CH(CF₃)— may be prepared by a process involvingintramolecular cyclization of the corresponding compound of formula(III) wherein, X¹ represents -hydroxy and wherein Q¹ represents—CH(OH)CF₃. The reaction is conveniently effected usingcyanomethylenetributylphosphorane, in a suitable solvent, e.g.tetrahydrofuran, at elevated temperature, e.g. 100° C.

Compounds of formula (I) wherein R¹² represents hydrogen, —X-Q-represents —O—C(═CH₂)— may be prepared by a process involvingintramolecular cyclization of the corresponding compound of formula(III) wherein, X¹ represents halogen, e.g. bromo, and wherein Q¹represents —CO—R and R represents CH₃.The reaction is convenientlyeffected in the presence of sodium hydride in a suitable solvent, e.g.tetrahydrofuran, at low temperature.

Intermediates of formula (III) wherein E represents (Ea) as definedabove, and X¹ represents hydroxy, may be prepared by a process whichcomprises the intramolecular cyclisation and desilylation of anintermediate of formula (IV),

wherein Z, R¹, R², R⁵, R⁶, R⁷, R⁸ and Q¹ are as defined above.

The reaction is suitably performed in the presence of tin(II) chlorideat elevated temperature in a polar solvent, e.g. ethanol.

Intermediate (IV) as defined above may be prepared by a processcomprising reacting intermediate (V),

wherein Q² represents —C(O)—H, and R¹, R², R⁵, R⁶, R⁷, R⁸ and Q¹ are asdefined above; with zinc iodide and triethylsilyl cyanide in thepresence of a base, e.g. triethylamine.

Typically, the intermediate of formula (V) wherein Q² represents —C(O)—Hmay be prepared from the corresponding intermediate wherein Q²represents —CO₂R^(h) and R^(h) represents C₁₋₆ alkyl, by reduction witha conventional reducing agent, e.g. a metal hydride, such asdiisobutyl-aluminium hydride (DIBAL-H).

The intermediate of formula (V) wherein Q² represents —CO₂R^(h) may beobtained by a process which comprises reacting an intermediate offormula (VI) with an intermediate of formula (VII),

wherein R¹, R², R⁵, R⁶, R⁷, R⁸, Z, Q¹ and Q² are as defined above; andL¹ is a suitable leaving group, e.g. a halogen atom, for examplebromine.

The reaction is conveniently performed in the presence of a base, e.g.an inorganic base, such as potassium carbonate, in a suitable solvent,e.g. an apolar solvent such as acetonitrile, at elevated temperature.

Intermediates of formula (VII) may be prepared by a multi-step processstarting from an intermediate of formula (VIII),

wherein R⁵, R⁶, R⁷, R⁸ and Q¹ are as defined above; which processcomprises the following steps:

-   -   (i) Reaction of intermediate (VIII) with (S)-t-butylsulfinamide        in the presence of K₃PO₄/KHPO₄ in a suitable solvent, e.g. THF;    -   (ii) Reacting the compound obtained from step (i) with a        compound of formula L²—Z-Q² , wherein Z and Q² are as defined        above and L² is a suitable leaving group, e.g. halogen, such as        bromine, and activated zinc metal dust prepared according to        conditions described in Hilpert, H. et al, Journal of Medicinal        Chemistry, 2013, 56(10), 3980-3995, in the presence of        transition metal salt, e.g. copper chloride at elevated        temperature;    -   (iii) Subsequent reaction with a strong mineral acid, e.g.        hydrogen chloride.

Intermediates of formula (VIII) wherein R⁵ represents halogen, e.g.chloro, may be transformed into the corresponding intermediate offormula (VIII) wherein R⁵ represents difluoromethoxy by a process whichcomprises (i) reaction with potassium hydroxide, in water at lowtemperature and (ii) reaction withdiethyl(bromodifluoromethyl)phosphonate, at low temperature.

Intermediates of formula (III) wherein E represents (Ea) as definedabove, and —X¹ represents —NH(R^(g)) and R^(g) represents hydrogen, maybe prepared by a process which comprises the reduction, intramolecularcyclization and desulfination of an intermediate of formula (IVa),

wherein Z, R¹, R², R⁵, R⁶, R⁷, R⁸ and Q¹ are as defined above.

The reaction is suitably performed in the presence of tin(II) chloride,followed by addition of a strong acid, e.g. hydrogen chloride, atelevated temperature in a polar solvent, e.g. ethanol.

Alternatively, the reduction and cyclization may be performed by aprocess involving (i) reduction using hydrogen under pressure, in thepresence of zinc bromine and of platinum on charcoal and (ii) additionof a strong acid, e.g. hydrogen chloride, at elevated temperature in apolar solvent, e.g. ethanol.

Intermediates of formula (IVa), may be prepared by a multi-step processstarting from corresponding intermediates (IVb),

wherein Z, R¹, R², R⁵, R⁶, R⁷, R⁸ and Q¹ are as defined above, and Vrepresents CH═CH₂, which process comprises:

-   -   (i) Reacting intermediate (IVb) with sodium periodate, in the        presence of potassium dioxide(dioxo)osmium hydrate and        2,6-dimethyl pyridine, followed by addition of sodium        thiosulfate, to afford corresponding intermediates of formula        (IVb) wherein V represents CH═O;    -   (ii) Reacting intermediates of formula (IVb) wherein V        represents CH═O with (R)-2-methylpropane-2-sulfinamide, in the        presence of a transition metal catalyst, eg. titanium (IV)        isopropoxide, in a suitable solvent, e.g. dichloromethane, to        afford corresponding intermediate of formula (IVb) wherein V        represents CH═N—(SO)-tert-butyl;    -   (iii) Further reaction with sodium cyanide, in the presence of        scandium triflate, in a suitable solvent, e.g. tetrahydrofuran,        to afford intermediates of formula (IVa).

Intermediates of formula (IVb) wherein Z, R¹, R², R⁵, R⁶, R⁷, R⁸ and Q¹are as defined above, and V represents CH=CH_(2,) may be prepared by aprocess comprising reacting intermediates of formula (VIIa),

wherein Z, V, R⁵, R⁶, R⁷, R⁸ and Q¹ are as defined above forintermediates of formula (IVb), with an intermediate of formula (VI) asdefined above, wherein L¹ is a halogen, e.g. fluorine, under conditionsanalogous to those described for the preparation of intermediates offormula (V).

Intermediates of formula (VIIa) may be prepared by a process analogousto the one described for intermediates of formula (VII), but wherein Q²is replaced by V.

Intermediates of formula (III), wherein E represents (Eb) or (Ec), asdefined above, and wherein X¹ represents hydroxy may be prepared fromintermediates of formula (IIIA),

wherein R⁵, R⁶, R⁷, R⁸, Z and Q¹ are as defined above; by reduction ofthe carbonyl moiety according to methods known to the person skilled inthe art.

Intermediates of formula (III) wherein X¹ represents —N H(R^(f)), R^(f)represents hydrogen and R¹² represents methyl may be prepared fromintermediate of formula (IIIA) using the following sequence of steps:

-   -   (i) Reacting intermediate of formula (IIIA) with        2-methyl-2-propanesulfinamide in the presence of Titanium (IV)        isopropoxide, in a solvent, e.g. tetrahydrofuran, at a suitable        temperature, e.g. 50° C.;    -   (ii) Adding a solution of methylmagnesium bromide, at low        temperature, in a suitable solvent, e.g. dichloromethane;    -   (iii) Removing the tert-butyl sulphinyl moiety in the presence        of a strong acid, e;g. HCl, in a suitable solvent, e.g.        1,4-dioxane.

Intermediates of formula (IIIA) may be prepared by a process whichcomprises intramolecular cyclization of an intermediate of formula (IX),

wherein A is N or C—R², Q³ is an electron withdrawing group, preferablyan ester moiety, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(h), Z and Q¹ areas defined above; in the presence of a base, in a suitable solvent atelevated temperature.

Intermediates of formula (IX) may be prepared by a process whichincludes reacting an intermediate of formula (X) with an intermediate offormula (XI),

wherein A, R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(h), Z, Q¹ and Q³ are asdefined above; and L³ is a suitable leaving group, typically a halogenatom, e.g. bromo.

The reaction is conveniently effected at an elevated temperature in asuitable solvent, e.g. a (C₁₋₄)alkanol such as ethanol, or an ether suchas 1,4-dioxane or dimethoxyethane, and in the presence of magnesiumsulphate.

Alternatively, intermediates of formula (IX), wherein Q³ is —CO₂H, maybe prepared according to a process which comprises reacting anintermediate of formula (XII),

wherein A, R¹, R³, R⁴, and R^(h) are as defined above; with anintermediate of formula (VIII) as defined above, in the presence ofMeldrum's acid, according to a method analogous to the one described ininternational patent application WO 2009/156091 or by M. Kerr et al. inJ. Org. Chem 2013, 78, 10534.

The reaction is conveniently effected in a suitable solvent e.g.acetonitrile, in the the presence of proline and magnesium sulphate, atelevated temperature, e.g. 80° C.

Where they are not commercially available, the starting materials offormula (VI), (VIII), (X), (XI) and (XII) may be prepared by methodsanalogous to those described in the accompanying Examples, or bystandard methods well known from the art.

Intermediates of formula (III) wherein X¹ represents amino, may beprepared from intermediates of formula (III) wherein X¹ is hydroxy, by aprocess which comprises (i) treatment with diphenylphosphorylazide and1,8-diazabicyclo[5.4.0]undec-7-ene, in a suitable solvent, e.g.tetrahydrofuran, at low temperature, e.g. 0° C., and (ii) subsequentaza-wittig reaction using triphenylphosphine, in a suitable solvent,e.g. a mixture of water and toluene.

Intermediates of formula (III), wherein E represents (Eb) or (Ec), asdefined above, and wherein X¹ represents amino may be prepared fromintermediates of formula (IIIA), wherein R⁵, R⁶, R⁷, R⁸, Z and Q¹ are asdefined above; by a process which comprises reacting intermediates offormula (IIIA) with a C₁₋₆ alkylsulfinamide, e.g.(R)-2-methylpropane-2-sulfinamide, in the presence of a transition metalcatalyst, e.g. titanium tetrakis ethanolate, in a suitable solvent, e.g.dichloromethane, followed by reduction with a suitable reducing agent,e.g. sodium borohydride, in a suitable solvent, e.g. tetrahydrofuran.

Intermediates of formula (III) wherein X¹ represents a leaving group Y,e.g. halogen or (C₁₋₆)alkylsulphonate, may be prepared fromintermediates of formula (III) wherein X¹ is hydroxy, according tostandard methods known to the person skilled in the art.

Intermediates of formula (III) wherein X¹ represents —SH, may beprepared from intermediates of formula (III) wherein X¹ is hydroxy or aleaving group Y, according to standard methods known to the personskilled in the art.

Intermediates of formula (III) wherein X¹ represents —CO₂H may beprepared by hydrolysis of corresponding intermediates of formula (III)wherein X¹ represents cyano, according to standard methods known to theperson skilled in the art.

Intermediates of formula (III) wherein X¹ represents cyano may beprepared by nucleophilic substitution of intermediates of formula (III)wherein X¹ represents a leaving group Y, and Y represents(C₁₋₆)alkylsulphonate-, according to standard methods known to theperson skilled in the art.

Intermediates of formula (III) wherein X¹ represents —CH₂OH may beprepared by reduction of the corresponding intermediate of formula (III)wherein X¹ represents -CO₂H, in the presence of a suitable reducingreagent, e.g., BH₃.

Intermediates of formula (III) wherein X¹ represents —CH₂-Y may beprepared from Intermediates of formula (III) wherein X¹ represents—CH₂OH, according to methods analogous to those described here above forintermediates of formula (III) wherein X¹ represents a leaving group Y,e.g. halogen or (C₁₋₆)alkylsulphonate.

Intermediates of formula (III) wherein X¹ represents —NH(R^(g)) andR^(g) represents —CO-(C₃₋₇)heterocycloalkyl may be prepared by reactingcompounds of formula (III) wherein X¹ represents —NH2 with a(C₃₋₇)heterocycloalkyl-COOH, in the presence of a base, e.g.N,N-diisopropylethylamine, and a coupling agent, e.g. HATU(N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]—N-ethylmethanaminiumhexafluorophosphate N-oxide), in a suitable solvent, e.g.dimethylformamide.

Intermediates of formula (III) wherein Q¹ represents formyl may beprepared from intermediates of formula (III) wherein Q¹ representshalogen, e.g. bromine, by a process involving (i) reaction withpotassium vinylfluoroborate, in the presence of a base and a transitionmetal catalyst and (ii) reaction with sodium periodate and osmiumtetraoxide, in the presence of a suitable solvent, e.g. a cyclic ether,such as 1,4-dioxane, at a suitable temperature, e.g. 0° C.

Suitable bases include inorganic bases, such as cesium carbonate andsuitable transition metal catalysts include1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethanecomplex.

Intermediates of formula (III) wherein Q¹ represents acetyl may beprepared from intermediates of formula (III) wherein Q¹ representshalogen, e.g. bromine, by a process involving (i) reaction withtributyl(1-ethoxyvinyl)tin, in the presence ofbis(triphenylphosphine)palladium(II)-dichloride, in a suitable solvent,e.g. toluene, at elevated temperature, and (ii) reaction with an acid,e.g. para-toluenesulphonic acid.

Intermediates of formula (III) wherein Q¹ represents—S-(CH₂)—(CH₂)—C(O)—O—CH₂—CH (CH₂CH₃) [(CH₂)₃CH₃], may be prepared fromintermediates of formula (III) wherein Q¹ represents halogen, e.g.bromine, by a process involving reaction with 3-mercaptopropionicacid-2-ethylester, in the presence of a suitable transition metalcatalyst, e.g. tris(benzylideneacetone)dipalladium(0) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, in a suitable solvent,e.g. 1,4-dioxane, at elevated temperature.

Similarly, intermediates of formula (III) wherein Q¹ represents—S—CH₂—C(O)—O—C₂H₅ [(CH₂)₃CH₃], may be prepared from intermediates offormula (III) wherein Q¹ represents halogen, e.g. bromine, by a processinvolving reaction with ethylthioglycolate, in the presence of asuitable transition metal catalyst, e.g.tris(benzylideneacetone)dipalladium(0) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, in a suitable solvent,e.g. 1,4-dioxane, at elevated temperature.

Intermediates of formula (III) wherein Q¹ represents —S—CH₃ may beprepared from intermediates of formula (III) wherein Q¹ representshalogen, e.g. bromine, by a process which involves treatment with sodiumthiomethoxide in a suitable solvent, e.g. dimethylsulphoxide, atelevated temperature.

Intermediates of formula (III) wherein Q¹ represents —CH(OH)—CF₃ may beprepared from intermediates of formula (III) wherein Q¹ represents—C(O)—H , by a process which involves reaction withtetrabutylammoniumfluoride, followed by(trifluoromethyl)trimethylsilane, in a suitable solvent, e.g.tetrahydrofuran, at low temperature.

It will be understood that any compound of formula (I) initiallyobtained from any of the above processes may, where appropriate,subsequently be elaborated into a further compound of formula (I) bytechniques known from the art.

As an alternative to the methods described here above, compounds offormula (I) wherein —X-Q- represents —O—CH₂— may be prepared by aprocess involving reduction of compounds of formula (I) wherein —X-Q-represents —O—C(O)-carried out according to the method described inSakai et al, J. Org. Chem. 2007, 72, 5920-5922 .

Compounds of formula (I) wherein —X-Q- represents —N(R^(g))—CH₂— may beprepared in a similar fashion from compounds of formula (I) wherein—X-Q- represents represents —N(R^(f))—CO— or under any other conditionsused for reduction of a lactam, known to the person skilled in the art.

Compounds of formula (I) wherein —X-Q- represents —S—, —CH₂—S— or—S—CH₂— may be transformed into compounds of formula (I) wherein —X-Q-represents respectively —SO— or —SO₂—; —CH₂—SO— or —CH₂—SO₂—; —SO—CH₂—or —SO₂—CH₂—, by performing oxidation according to methods known to theperson skilled in the art.

Compounds of formula (I) wherein —X-Q- represents —SO-, —CH₂—SO— or—SO-CH₂— may be transformed into compounds of formula (I) wherein —X-Q-represents respectively —S(O)(NH)—, —CH₂—S(O)(NH)—, or —S(O)(NH)—CH₂—,by a method analogous to that described in Okamura, H. et al, OrganicLetters, 2004 , 6(8),1305-1307.

Compounds of formula (I) wherein —X-Q- represents —S— may be transformedinto compounds of formula (I) wherein —X-Q- represents —S(═N—CN)— by aprocess involving reaction with iodobenzene diacetate, in the presenceof cyanamide. The reaction is conveniently effected in acetonitrile atlow temperature, e.g. 0° C.

Compounds of formula (I) wherein —X-Q- represents —N(R^(f))—C(O)— may beconverted into the corresponding compound of formula (I) wherein —X-Q-represents —N(R^(f))—C(S)— by treatment with Lawesson's reagentaccording to methods known to the skilled person in the art.

Compounds of formula (I) wherein —X-Q- represents —NH— may be furthertransformed into compounds of formula (I) wherein —X-Q- represents—N(R^(g))— wherein R^(g) is an optionally substituted —CO—(C₁₋₆)alkyl,by reaction with chloracetyl chloride, in a suitable solvent, e.g.dichloromethane. Substituents may subsequently be introduced on the(C₁₋₆)alkyl moiety by treatment with a suitable base according to amethod analogous to the ones described in the accompanying Examples.

Compounds of formula (I) or intermediates of formula (III) wherein R^(f)or R^(g) represent hydrogen, may further be transformed into thecorresponding compounds of formula (I) or intermediates of formula (III)wherein R^(f) or R^(g) represent optionally substituted C₁₋₆ alkyl, orits deuterated equivalent , by reaction with the correspondingoptionally substituted C₁₋₆ alkyl halide or deuterated equivalent, e.g.C₁₋₆ alkyl iodide or its deuterated equivalent, in the presence of abase, e.g. cesium carbonate or potassium bis(trimethylsilyl)amide(KHMDS), in a suitable solvent, e;g., dimethylformamide or THF

Compounds of formula (I) or intermediates of formula (III) wherein R^(f)or R^(g) represent hydrogen, may further be transformed into thecorresponding compounds of formula (I) or intermediates of formula (III)wherein R^(f) or R^(g) represent acetyl by reaction with aceticanhydride, in the presence of base, e.g. pyridine, in a suitablesolvent, e.g. dichloromethane.

Compounds of formula (I) or intermediates of formula (III) wherein R^(f)or R^(g) represent hydrogen, may further be transformed into thecorresponding compounds of formula (I) or intermediates of formula (III)wherein R^(f) or R^(g) represent methyl, by reaction with formaldehyde,in a suitable solvent, e.g. 2,2,2-trifluoroethanol, followed by reactionwith a suitable reducing agent, e.g. sodium borohydride.

Compounds of formula (I) or intermediates of formula (III) wherein R^(f)or R^(g) represent hydrogen, may further be transformed into thecorresponding compounds of formula (I) or intermediates of formula (III)wherein R^(f) or R^(g) represent (C₁₋₆)alkyl-sulphonyl by treatment withthe appropriate (C₁₋₆) alkylsulphonyl halide, e.g. methane sulphonylchloride, in the presence of a suitable base, e.g.N,N-diisopropylethylamine or triethylamine, in a suitable solvent e.g.dichloromethane.

A compound of formula (I) or an intermediate of formula (III) whichcontains a hydroxy group may be alkylated by treatment with theappropriate alkyl halide in the presence of a base, e.g. sodium hydride,or silver oxide.

A compound of formula (I) or an intermediate of formula (III) whichcontains hydroxy may be converted into the correspondingfluoro-substituted compound by treatment with diethylamino sulfurtrifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (BAST).A compound of formula (I) which contains hydroxy may be converted intothe corresponding difluoro-substituted compound via a two-step procedurewhich comprises: (i) treatment with an oxidising agent, e.g. manganesedioxide; and (ii) treatment of the carbonyl-containing compound therebyobtained with DAST.

A compound of formula (I) or an intermediate of formula (III) whichcontains an N—H moiety may be alkylated by treatment with theappropriate alkyl halide, typically at an elevated temperature in anorganic solvent such as acetonitrile; or at ambient temperature in thepresence of a base, e.g. potassium hydroxide, in a suitable solvent,e.g. THF, in the presence of tetra-butylammonium bromide; or at elevatedtemperature in the presence of a base, e.g. sodium hydride, with orwithout tetra-butylammonium iodate, in a suitable solvent, e.g. THF; orat elevated temperature in the presence of a an alkali metal carbonatesuch as potassium carbonate or cesium carbonate, in a suitable solvent,e.g. a dipolar aprotic solvent such as N,N-dimethylformamide. A compoundof formula (I) which contains an N—H moiety may be methylated bytreatment with formaldehyde in the presence of a reducing agent, e.g.sodium triacetoxyborohydride.

A compound of formula (I) or an intermediate of formula (III) whichcontains an N—H moiety may be acylated by treatment with the appropriateacid chloride, e.g. acetyl chloride, or with the appropriate carboxylicacid anhydride, e.g. acetic anhydride, typically at ambient temperaturein the presence of a base, e.g. an organic base such as triethylamine.

A compound of formula (I) or an intermediate of formula (III) whichcontains an N—H moiety may be converted into the corresponding compoundwherein the nitrogen atom is substituted by C₁₋₆ alkyl-sulphonyl, e.g.methylsulphonyl, by treatment with the appropriate C₁₋₆ alkylsulphonylchloride, e.g. methanesulphonyl chloride, or with the appropriate C₁₋₆alkylsulphonic acid anhydride, e.g. methanesulphonic anhydride,typically at ambient temperature in the presence of a base, e.g. anorganic base such as triethylamine or N,N-diisopropylethyl-amine.

A compound of formula (I) or an intermediate of formula (III) whichcontains an N—H moiety may be converted into the corresponding compoundwherein the nitrogen atom is substituted by C₁₋₆ alkoxy-carbonyl, e.g.methoxycarbonyl, by treatment with the corresponding C₁₋₆alkoxy-carbonyl halide, in the presence of a base, e.g. potassiumcarbonate, in a suitable solvent, e.g., N, N′-dimethylformamide.

A compound of formula (I) or an intermediate of formula (III)substituted by amino (—NH₂) may be converted into the correspondingcompound substituted by C₁₋₆ alkylsulphonylamino, e.g.methylsulphonyl-amino, or bis[(C₁₋₆)alkylsulphonyl]amino, e.g.bis(methylsulphonyl)amino, by treatment with the appropriate C₁₋₆alkylsulphonyl halide, e.g. a C₁₋₆ alkylsulphonyl chloride such asmethanesulphonyl chloride, in the presence of a suitable base, e.g.N,N-diisopropylethylamine, in a suitable solvent e.g. dichloromethane

Similarly a compound of formula (I) or an intermediate of formula (III)substituted by amino may be transformed into the corresponding compoundof formula (I) or intermediate of formula (III) substituted byNH—SO₂—(C₃₋₇)cycloalkyl, NH —SO₂-(C₃₋₇)heterocycloalkyl, NH-SO₂-aryl orNH—SO₂-heteroaryl respectively from the corresponding(C₃₋₇)cycloalkyl-sulphonylhalide, (C₃₋₇)heterocycloalkyl-sulphonylhalide, aryl-sulphonyl-halide or heteroaryl-sulphonyl-halide.

Similarly, a compound of formula (I) substituted by hydroxy (-OH) may beconverted into the corresponding compound substituted by C₁₋₆alkyl-sulphonyloxy, e.g. methylsulphonyloxy, by treatment with theappropriate C₁₋₆ alkyl-sulphonyl halide, e.g. a C₁₋₆ alkylsulphonylchloride such as methanesulphonyl chloride.

A compound of formula (I) or an intermediate of formula (III)substituted by amino (—NH₂) may be converted into the correspondingcompound substituted by (tert-butyl)(dimethyl)silyloxyethyl-NH— bytreatment with (bromoethoxy)-tert-butyldimethylsilane, in the presenceof a suitable base, e.g. potassium carbonate, in a suitable solvent,e.g. dimethyl formamide, at elevated temperature.

A compound of formula (I) or an intermediate of formula (III) containingthe moiety —S— may be converted into the corresponding compoundcontaining the moiety —S(O)— by treatment with 3-chloroperoxy-benzoicacid. Likewise, a compound of formula (I) containing the moiety —S(O)—may be converted into the corresponding compound containing the moiety—S(O)₂— by treatment with 3-chloroperoxybenzoic acid. Alternatively, acompound of formula (I) containing the moiety —S— may be converted intothe corresponding compound containing the moiety —S(O)₂— by treatmentwith Oxone® (potassium peroxymonosulfate).

A compound of formula (I) or an intermediate of formula (III) containingan aromatic nitrogen atom may be converted into the correspondingN-oxide derivative by treatment with 3-chloroperoxy-benzoic acid.

A compound of formula (I) or an intermediate of formula (III) whichcontains a carbonyl may be converted into the corresponding alcohol bytreatment with a suitable borohydride, e.g.lithium-tri-sec-butyl-borohydride or sodium borohydride, in a suitablesolvent e.g. THF.A compound of formula (I) or an intermediate of formula(III) wherein R¹ represents halogen, e.g. bromo, may be converted intothe corresponding compound wherein R¹ represents an optionallysubstituted aryl or heteroaryl moiety by treatment with theappropriately substituted aryl or heteroaryl boronic acid or a cyclicester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediolor neopentyl glycol. The reaction is typically effected at elevatedtemperature in the presence of a transition metal catalyst, e.g. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),tetrakis(triphenylphosphine)palladium(0), orbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, and a base, e.g. an inorganic base such as sodium carbonate,potassium carbonate or cesium carbonate, or potassium phosphate, in asuitable solvent, e.g. 1,4-dioxane or a mixture of 1,4-dioxane andwater.

Alternatively, a compound of formula (I) or an intermediate of formula(III) wherein R¹ represents halogen, e.g. bromo, may be converted intothe corresponding compound wherein R¹ represents an optionallysubstituted aryl or heteroaryl moiety by treatment with theappropriately substituted aryl or heteroaryl boronic acid, in thepresence of a transition metal catalyst, e.g.tris(dibenzylideneacetone)dipalladium(0), andtricyclohexylphosphoniumtetrafluoroborate, in the presence of a base,e.g. potassium phosphate, in a suitable solvent, e.g. cyclic ether, suchas 1,4-dioxane. The reaction is conveniently effected at elevatedtemperature and microwave technology may be used.A compound of formula(I) wherein R¹ represents 2-oxo-(1H)-pyridinyl may be obtained bytreatment of the corresponding compound of formula (I) wherein R¹represents 2-methoxy-pyridinyl, with pyridine hydrochloride at elevatedtemperature, e.g. 160° C.

A compound of formula (I) or an intermediate of formula (III) wherein R¹represents an ester moiety may be obtained by reacting the correspondingcompound of formula (I) or the intermediate of formula (III) wherein R¹is halogen, e.g. chloride, with a base, e.g. sodium carbonate, and thecorresponding alcohol moiety in the presence of a transition metalcatalyst, typically bis(dicyclohexylphosphino)propane]palladium(II).

A compound of formula (I) or an intermediate of formula (III) wherein R¹represents cyano may be obtained by reacting the corresponding compoundof formula (I) or the intermediate of formula (III) wherein R¹ ishalogen, e.g. chloride, with zinc cyanide, in the presence of atransition metal catalyst, e.g. tetrakis(triphenylphosphine)palladium,in a suitable solvent, e.g., N,N-dimethylformamide. The reaction isconveniently effected at elevated temperature, e.g. 180° C., usingmicrowave technology.

In general, a compound of formula (I) containing a —C═C-functionalitymay be converted into the corresponding compound containing a—CH—CH-functionality by catalytic hydrogenation, typically by treatmentwith a hydrogenation catalyst, e.g. palladium on charcoal, under anatmosphere of hydrogen gas, optionally in the presence of a base, e.g.an alkali metal hydroxide such as sodium hydroxide.

A compound of formula (I) containing an ester moiety, e.g. a C₂₋₆alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may beconverted into the corresponding compound containing a carboxy (—CO₂H)moiety by treatment with an acid, e.g. a mineral acid such ashydrochloric acid.

A compound of formula (I) containing an ester moiety, e.g. a C₂₋₆alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, mayalternatively be converted into the corresponding compound containing acarboxy (—CO₂H) moiety by treatment with a base, e.g. an alkali metalhydroxide selected from lithium hydroxide, sodium hydroxide andpotassium hydroxide; or an organic base such as sodium methoxide orsodium ethoxide.

A compound of formula (I) containing a carboxy (—CO₂H) moiety may beconverted into the corresponding compound containing an amide moiety bytreatment with the appropriate amine in the presence of a condensingagent such as 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide.

A compound of formula (I) containing a carbonyl (C═O) moiety may beconverted into the corresponding compound containing a —C(CH₃)(OH)—moiety by treatment with methylmagnesium bromide. Similarly, a compoundof formula (I) containing a carbonyl (C═O) moiety may be converted intothe corresponding compound containing a —C(CF₃)(OH)— moiety by treatmentwith (trifluoromethyl)trimethylsilane and cesium fluoride. A compound offormula (I) containing a carbonyl (C═O) moiety may be converted into thecorresponding compound containing a —C(CH₂NO₂)(OH)— moiety by treatmentwith nitromethane.

A compound of formula (I) containing a hydroxymethyl moiety may beconverted into the corresponding compound containing a formyl (—CHO)moiety by treatment with an oxidising agent such as Dess-Martinperiodinane. A compound of formula (I) containing a hydroxymethyl moietymay be converted into the corresponding compound containing a carboxymoiety by treatment with an oxidising agent such as tetrapropylammoniumperruthenate.

A compound of formula (I) containing an aryl or an heteroaryl moiety maybe transformed into the corresponding compound containing an aryl orheteroaryl moiety where a hydrogen atom has been substituted by a chloroor bromo substituent by reaction respectively with N-chlorosuccinimideor N-bromosuccinimide, in a suitable solvent , e.g. dimethylformamide,according to methods known to the person skilled in the art.

A compound of formula (I) containing an aryl moiety bearing adifluoromethoxy group may be transformed into the corresponding compoundcontaining an aryl moiety where the difluoromethoxy group has beensubstituted by a hydroxy group, by reaction withsodiumbis(trimethylsilyl)amide, in a suitable solvent, e.g. THF, at lowtemperature.

A compound of formula (I) containing an aryl or an heteroaryl moiety maybe transformed into the corresponding compound containing an aryl orheteroaryl moiety where a hydrogen atom has been substituted by atrifluoromethyl substituent by reaction respectively with (i)trifluoroacetic acid in a suitable solvent, e.g. acetonitrile, (ii)addition of trifluoromethanesulphonyl chloride, followed by[4,4′-Bis(tert-butyl)-2,2′-bipyridine]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl]phenyl]iridium(III)hexafluorophosphate, according to conditions analogous to thosedescribed by McMillan ate al. in Nature, 2011, 480, 224.

In one embodiment, the present invention provides compounds of formula(I), in particular compounds of formula (IB), (IC) or (ID) as definedabove, wherein R¹ represents a substituted heteroaryl selected from thegroups represented by formula (i), (ii), (iii), (iv) and (v), and theirrespective corresponding salts represented by formula (ia), (ib), (iia),(iiia), (iva), (va), and (vb):

wherein

the asterisk (*) represents the site of attachment of R¹ to theremainder of the molecule;

W and R¹⁰ are as defined above;

R¹¹ represents C₁₋₆ alkyl;

M¹ represents a monovalent cation; and

M²represents a divalent cation.

In a first aspect of this embodiment, the present invention relates tocompounds of formula (I) wherein R¹ is heteroaryl substituted byphosphate-C₁₋₆ alkyl, e.g., represented by the group of formula (i), orsalts thereof, represented respectively by groups of formula (ia) or(ib).

In a second aspect of this embodiment, the present invention relates tocompounds of formula (I) wherein R¹ is heteroaryl substituted by C₁₋₆alkyl phosphate-C₁₋₆ alkyl e.g., represented by the group of formula(ii), or salts thereof, represented by formula (iia).

In a third aspect of this embodiment, the present invention relates tocompounds of formula (I) wherein R¹ is heteroaryl substituted bysulphate-C₁₋₆ alkyl, e.g. as represented by the group of formula (iii),or salts thereof represented by formula (iiia).

In a fourth aspect of this embodiment, the present invention relates tocompounds of formula (I) wherein R¹ is heteroaryl substituted bycarboxy-(C₁₋₆)alkyl-carbonyloxy-C₁₋₆ alkyl, e.g. as represented by thegroup of formula (iv), or salts thereof represented by formula (iva).

In a fifth aspect of this embodiment, the present invention relates tocompounds of formula (I) wherein R¹ is heteroaryl substituted byphosphate-methoxy-C₁₋₆ alkyl, e.g., as represented by the group offormula (v), or salts thereof represented respectively by the groups offormula (va) or (vb).

Typical examples of monovalent cation M¹ in accordance with the presentinvention include alkali metal cations or cations represented by formula⁺NH(R^(k))₃ wherein R^(k) represents hydrogen or C₁₋₆ alkyl.

Suitably, R¹¹ represents ethyl.

In a first embodiment M¹ represents Na⁺. In a second embodiment, M¹represents K⁺. In a third embodiment, M¹ represents ⁺NH₄. In a fourthembodiment M¹ represents ⁺NH(C₁₋₆alkyl)₃. In a particular aspect of thisembodiment, M¹ represents ⁺NH(CH₂CH₃)₃.

Suitably, M¹ represents Na⁺.

Typical examples of divalent cations M² in accordance with the presentinvention include alkaline earth metal cations.

Suitably, M² represents Ca²⁺.

In a particular aspect of this embodiment, the present invention relatesto compounds of formula (I), in particular compounds of formula (IB),(IC) or (ID) as defined above, wherein R¹ represents a substitutedheteroaryl selected from the groups represented by formula (i), (iii),(iv), and their respective salts of formula (iiia), (va) and (vb).

A compound of formula (I) wherein R¹ is heteroaryl substituted byphosphate-C 1.6 alkyl, e.g., as represented above by formula (i) may beprepared from the corresponding compound of formula (I) wherein R¹ issubstituted by hydroxy-C₁₋₆ alkyl by i) treatment with di benzylN,N-di-isopropylphosphoramidite in a suitable solvent, e.g.

dichloromethane, followed by treatment with hydrogen peroxide at lowtemperature and ii) subsequent hydrogenolysis, e.g. using hydrogen gasunder pressure, in the presence of a suitable catalyst, e.g. palladiumon charcoal, according to a method analogous to those described by S. P.Green et al. in Organic Process Research & Development, 2002, 6,109-112. A compound of formula (I) wherein R¹ is heteroaryl substitutedby a salt of phosphate-C₁₋₆ alkyl, e.g. as represented by formula (ia)or formula (ib) above, wherein M¹ and M² are independently alkali metalcation or alkaline earth metal cation, may be prepared by performing theabove described hydrogenolysis step (ii) in the presence of a suitablealkali metal base or alkaline earth metal base. A compound of formula(I) wherein R¹ is heteroaryl substituted by C₁₋₆ alkyl phosphate-C₁₋₆alkyl, e.g. as represented above by formula (ii), may be prepared fromthe corresponding compound of formula (I) wherein R¹ is substituted byhydroxy-C₁₋₆ alkyl by: i) first reacting cyanoethylphosphoramidite witha compound of formula R¹¹—OH, in the presence of diisopropylethylaminein a suitable solvent e.g. dichloromethane, ii) addition of compound offormula (I) wherein R¹ is substituted by hydroxy-C₁₋₆ alkyl in thepresence of a suitable solvent, e.g. dichloromethane, (iii) followed byoxidation and subsequent treatment with a suitable base, according to amethod analogous to those described by Nam, N—H. et al. in Bio-org. MedChem., 2004, 12, 6255 or Bennani, L. et al. in international patentapplication WO 2012/177707 A1.

A compound of formula (I) wherein R¹ is heteroaryl substituted bysulphate-C₁₋₆ alkyl, e.g. as represented above by formula (iii), may beprepared by treatment of the corresponding compound of formula (I)wherein R¹ is substituted by hydroxy-C₁₋₆ alkyl, with pyridine:sulphurtrioxide complex, according to a method analogous to the one describedby E. Lacko et al. in Current Medicinal Chemistry, 2012, 19, 4699, oralternatively, by treatment with chloro sulphonic acid in the presenceof triethylamine, according to a method analogous to the one describedin C. Guo et al. in international patent application WO 2004/087720 A1.

A compound of formula (I) wherein R¹ is heteroaryl substituted bycarboxy(C₁₋₆)alkyl-carbonyloxy-C₁₋₆ alkyl e.g. as represented by thegroup of formula (iv), may be prepared by reacting the correspondingcompound of formula (I) wherein R¹ is substituted by hydroxy-C₁₋₆ alkyl,with an appropriate anhydride, e.g. succinic anhydride, in the presenceof dimethylaminopyridine, in a suitable solvent, e.g. pyridine, atelevated temperature, according to a method analogous to the onedescribed by C. Liu et al., in Molecular Pharmaceutics, 2014, 57, 7509or W. N. Washburn et al. in J. Med. Chem, 2014, 57, 7509.

A compound of formula (I) wherein R¹ is heteroaryl substituted byphosphate-methoxy-C₁₋₆ alkyl e.g. as represented by the group of formula(v), may be prepared by reacting the corresponding compound of formula(I) wherein R¹ is substituted by hydroxy-C₁₋₆ alkyl, with a suitablebase, e.g. sodium hydride, in a suitable solvent, e.g. dimethoxyethane,followed by addition of chloromethyldi-tert-butyl-phosphate, andsubsequent dealkylation, at high temperature, according to a methodanalogous to the one described in international patent application WO2012/135082 A1.

Compounds of formula (I) wherein R¹ is heteroaryl substituted byphosphate-C₁₋₆ alkyl, e.g. as represented by formula (i), which can beisolated as a result of the above hydrogenolysis step (ii), may betransformed into the corresponding compound of formula (I) wherein R¹ isheteroaryl substituted by a salt of phosphate-C₁₋₆ alkyl, e.g. asrepresented by formula (ia) wherein M¹ represents an alkali metal cationor a cation of formula ⁺NH(R^(k))₃ or may be transformed into thecorresponding compound of formula (I) wherein R¹ is heteroarylsubstituted by a salt of phosphate-C₁₋₆ alkyl, e.g., as represented byformula (ib), wherein M² represents an alkaline earth metal cation, bytreatment with the corresponding base, i.e. respectively an alkali metalbase or the corresponding base of formula N(R^(k))₃ or an alkaline earthmetal base, in a suitable solvent according to methods known to theperson skilled in the art.Suitable alkali metal bases include sodiumhydroxide and potassium hydroxide.

Suitable alkaline earth metal bases include calcium hydroxide.

Suitable bases of formula N(R^(k))₃ include ammonia (NH₃) andtriethylamine.

Compounds of formula (I) wherein R¹ is heteroaryl substitutedindependently by C₁₋₆ alkyl phosphate-C₁₋₆ alkyl, e.g. as represented bythe group of formula (ii), or by sulphate-C₁₋₆ alkyl, e.g. asrepresented by the group of formula (iii), or bycarboxy(C₁₋₆)alkyl-carbonyloxy-C₁₋₆ alkyl, e.g. as represented by thegroup of formula (iv), or by phosphate-methoxy-C₁₋₆ alkyl, e.g. asrepresented by the group of formula (v), may be transformed into theirrespective corresponding salts represented by formula (iia), (iiia),(iva), (va) and (vb), according to a method analogous to the onedescribed above for compounds of formula (I) wherein R¹ is heteroarylsubstituted by phosphate-C₁₋₆ alkyl.

Illustrative examples of compounds according to the present inventionwherein R¹ is a substituted heteroaryl selected from the groupsrepresented by formula (i), (ii), (iii), (iv) and (v), and theirrespective salts of formula (ia), (ib), (iia), (iiia), (iva), (va) asdefined above, include the following compounds:

Where a mixture of products is obtained from any of the processesdescribed above for the preparation of compounds according to theinvention, the desired product can be separated therefrom at anappropriate stage by conventional methods such as preparative HPLC; orcolumn chromatography utilising, for example, silica and/or alumina inconjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques. In particular,where it is desired to obtain a particular enantiomer of a compound offormula (I) this may be produced from a corresponding mixture ofenantiomers using any suitable conventional procedure for resolvingenantiomers. Thus, for example, diastereomeric derivatives, e.g. salts,may be produced by reaction of a mixture of enantiomers of formula (I),e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.The diastereomers may then be separated by any convenient means, forexample by crystallisation, and the desired enantiomer recovered, e.g.by treatment with an acid in the instance where the diastereomer is asalt. In another resolution process a racemate of formula (I) may beseparated using chiral HPLC. Moreover, if desired, a particularenantiomer may be obtained by using an appropriate chiral intermediatein one of the processes described above. Alternatively, a particularenantiomer may be obtained by performing an enantiomer-specificenzymatic biotransformation, e.g. an ester hydrolysis using an esterase,and then purifying only the enantiomerically pure hydrolysed acid fromthe unreacted ester antipode. Chromatography, recrystallisation andother conventional separation procedures may also be used withintermediates or final products where it is desired to obtain aparticular geometric isomer of the invention. Alternatively the nondesired enantiomer may be racemized into the desired enantiomer, in thepresence of an acid or a base, according to methods known to the personskilled in the art, or according to methods described in theaccompanying Examples.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W.Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley& Sons, 3^(rd) edition, 1999. The protecting groups may be removed atany convenient subsequent stage utilising methods known from the art.

Compounds in accordance with the present invention potently neutralisethe activity of TNFα in a commercially available HEK-293 derivedreporter cell line known as HEK-Blue™ CD40L. This is a stable HEK-293transfected cell line expressing SEAP (secreted embryonic alkalinephosphatase) under the control of the IFNIβ minimal promoter fused tofive NF-κB binding sites. Secretion of SEAP by these cells is stimulatedin a concentration-dependent manner by TNFα. When tested in the HEK-293bioassay, also referred to herein as the reporter gene assay, compoundsof the present invention exhibit an IC₅₀ value of 50 μM or less,generally of 20 μM or less, usually of 5 μM or less. typically of 1 μMor less, suitably of 500 nM or less, ideally of 100 nM or less, andpreferably of 25 nM or less (the skilled person will appreciate that alower IC₅₀ figure denotes a more active compound).

Certain compounds in accordance with the present invention potentlyinhibit the binding of a fluorescence conjugate to TNFα when tested inthe fluorescence polarisation assay described herein. Indeed, whentested in that assay, compounds of the present invention exhibit an IC₅₀value of 50 μM or less, generally of 20 μM or less, usually of 5 μM orless, typically of 1 μM or less, suitably of 500 nM or less, ideally of100 nM or less, and preferably of 25 nM or less (as before, the skilledperson will appreciate that a lower IC₅₀ figure denotes a more activecompound).

The compounds of the Examples have been tested in one or both of theassays described below.

Fluorescence Polarisation Assay

-   Preparation of Compound (A)

1-(2,5-Dimethylbenzyl)-6-[4-(piperazin-1-ylmethyl)phenyl]-2-(pyridin-4-yl-methyl)-1H-benzimidazole—hereinafterreferred to as “Compound (A)”—can be prepared by the procedure describedin Example 499 of WO 2013/186229; or by a procedure analogous thereto.

-   Preparation of Fluorescence Conjugate

Compound (A) (27.02 mg, 0.0538 mmol) was dissolved in DMSO (2 mL). 5(−6) Carboxy-fluorescein succinimyl ester (24.16 mg, 0.0510 mmol)(Invitrogen catalogue number: C1311) was dissolved in DMSO (1 mL) togive a bright yellow solution. The two solutions were mixed at roomtemperature, the mixture turning red in colour. The mixture was stirredat room temperature. Shortly after mixing a 20 _(i)lL aliquot wasremoved and diluted in a 80:20 mixture of AcOH:H20 for LC-MS analysis onthe 1200RR-6140 LC-MS system. The chromatogram showed two closelyeluting peaks at retention times of 1.42 and 1.50 minutes, both withmass (M+H)⁺=860.8 amu, corresponding to the two products formed with the5- and 6-substituted carboxyfluorescein group. A further peak atretention time 2.21 minutes had a mass of (M+H)⁺=502.8 amu,corresponding to Compound (A). No peak was observed for unreacted 5(-6)carboxyfluorescein succinimyl ester. The peak areas were 22.0%, 39.6%and 31.4% for the three signals, indicating a 61.6% conversion to thetwo isomers of the desired fluorescence conjugate at that time-point.Further 20 uL aliquots were extracted after several hours and then afterovernight stirring, diluted as before and subjected to LC-MS analysis.The percentage conversion was determined as 79.8% and 88.6% respectivelyat these time-points. The mixture was purified on a UV-directedpreparative HPLC system. The pooled purified fractions were freeze-driedto remove excess solvent. After freeze-drying, an orange solid (23.3 mg)was recovered, equivalent to 0.027 mmol of fluorescence conjugate,corresponding to an overall yield of 53% for the reaction andpreparative HPLC purification.

-   Inhibition of Binding of Fluorescence Conjugate to TNFα

Compounds were tested at 10 concentrations starting from 25 μM in afinal assay concentration of 5% DMSO, by pre-incubation with TNFα for 60minutes at ambient temperature in 20 mM Tris, 150 mM NaCl, 0.05% Tween20, before addition of the fluorescence conjugate and a furtherincubation for 20 hours at ambient temperature. The final concentrationsof TNFα and the fluorescence conjugate were 10 nM and 10 nM respectivelyin a total assay volume of 25 μL. Plates were read on a plate readercapable of detecting fluorescence polarisation (e.g. an Analyst HT platereader; or an Envision plate reader). An IC₅₀ value was calculated usingXLfit™ (4 parameter logistic model) in ActivityBase.

When tested in the fluorescence polarisation assay, compounds of theaccompanying Examples were found to exhibit IC₅₀ values of 50 μM orbetter.

When tested in the fluorescence polarisation assay, compounds of theaccompanying Examples exhibit IC₅₀ values generally in the range ofabout 0.01 nM to about 50 μM, usually in the range of about 0.01 nM toabout 20 μM, typically in the range of about 0.01 nM to about 5 μM,suitably in the range of about 0.01 nM to about 1 μM, ideally in therange of about 0.01nM to about 500 nM, appositely in the range of about0.01nM to about 100 nM, and preferably in the range of about 0.01nM toabout 25 nM.

Reporter Gene Assay

-   Inhibition of TNFα -Induced NE-κB Activation

Stimulation of HEK-293 cells by TNFα leads to activation of the NF-κBpathway. The reporter cell line used to determine TNFα activity waspurchased from InvivoGen. HEK-Blue™ CD4OL is a stable HEK-293transfected cell line expressing SEAP (secreted embryonic alkalinephosphatase) under the control of the IFNβ minimal promoter fused tofive NF-κB binding sites. Secretion of SEAP by these cells is stimulatedin a dose-dependent manner by TNFα, with an EC50 of 0.5 ng/mL for humanTNFα. Compounds were diluted from 10 mM DMSO stocks (final assayconcentration 0.3% DMSO) to generate a 10-point 3-fold serial dilutioncurve (30,000 nM to 2 nM final concentration, for example). Dilutedcompound was preincubated with TNFα for 60 minutes prior to addition toa 384-well microtitre plate and incubated for 18 h. The final TNFαconcentration in the assay plate was 0.5 ng/mL. SEAP activity wasdetermined in the supernatant using the colorimetric substratesQUANTI-Blue™ or HEK-Blue™ Detection media (InvivoGen). Percentageinhibitions for compound dilutions were calculated between a DMSOcontrol and maximum inhibition (by excess control compound) and an IC₅₀value calculated using XLfit™ (4 parameter logistic model) inActivityBase.

When tested in the reporter gene assay, the compounds of theaccompanying Examples were all found to exhibit IC₅₀ values of 50 μM orbetter.

When tested in the reporter gene assay, compounds of the accompanyingExamples exhibit IC₅₀ values generally in the range of about 0.01 nM toabout 50 μM, usually in the range of about 0.01 nM to about 20 μM,typically in the range of about 0.01 nM to about 5 μM, usually in therange of about 0.01 nM to about 1 μM, suitably in the range of about0.01nM to about 500 nM, ideally in the range of about 0.01nM to about100 nM, and appositely in the range of about 0.01nM to about 25 nM.

The following Examples illustrate the preparation of compounds accordingto the invention.

EXAMPLES

Abbreviations DCM: Dichloromethane EtOAc: Ethyl acetate DMF:N,N-Dimethylformamide MeOH: Methanol DMSO: Dimethylsulfoxide SiO2:Silica Et2O: Diethyl ether h: Hour THF: Tetrahydrofuran AcOH: Aceticacid r.t.: Room temperature b s.: Broad singlet M: Mass Brine: Saturatedaqueous sodium chloride solution HPLC: High Performance LiquidChromatography LCMS: Liquid Chromatography Mass Spectrometry ES+:Electrospray Positive Ionisation TEA: Triethylamine DIPEA:N,N-di-iso-propylethylamine DIAD: Diisopropyl(E)-1,2-diazenedicarboxylate RT: retention time TBAF: tetrabutylammonium fluoride TLC: Thin Layer Chromatography MeCN: AcetonitrileDIBAL-H: Diisobutylaluminium hydride TMSCN: Trimethylsilyl cyanide DEA:Diethanolamine pTSA para-toluene sulphonic acid monohydrate TFA:trifluoroacetic acid DMA: dimethyl acetamide HATU:N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-ethylmethanaminium hexafluorophosphate N-oxide KHMDS: Potassiumbis(trimethylsilyl)amide COMU: (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino carbenium hexafluorophosphate PdCl₂(dcypp):dichloro-bis(dicyclohexylphosphino)propane] palladium(II)[Ir{dF(CF₃)ppy}₂(dtbpy)]PF₆[4,4′-Bis(tert-butyl)-2,2′-bipyridine]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridinyl]phenyl]iridium(III)hexafluorophosphate

Analytical Conditions

All NMRs were obtained either at 300 MHz or 400 MHz.

All reactions involving air-or moisture-sensitive reagents wereperformed under a nitrogen atmosphere using dried solvents andglassware.

All compound LCMS data was determined by using the method below:

Method 1: For Intermediates 1 to 7 and 15 to 17.

Shimadzu 2010-YMC Triart C18, 4.6×50 mm, 3 μm column

Mobile phase A: 10 mM Ammonium Formate +0.1% Ammonia +water

Mobile phase B: 5% of mobile phase A +95% MeCN +0.1% Ammonia

Gradient program (Flow Rate 1.4 mL/min, Column Temperature 40° C.):

Time A % B % 0.1 70 30 2.5 5 95 3.5 5 95 5.0 70 30 5.5 70 30

Method 2: For Intermediate 8 and 18

Shimadzu 2010—X-bridge C18 Waters 2.1×20 mm, 2.5 μm column

Mobile phase A: 10 mM Ammonium Formate +0.1% Ammonia +water

Mobile phase B: 5% of mobile phase A +95% MeCN +0.1% Ammonia

Gradient program (Flow Rate 1.0 mL/min, Column Temperature 40° C.):

Time A % B % 0.1 95 5 4.0 5 95 5.0 5 95 5.1 95 5 6.5 95 5

Method 3 for All Analytical LCMS Done in Basic Conditions: LCMS Basic:

A QDA Waters simple quadrupole mass spectrometer is used for LC-MSanalysis.

This spectrometer is equipped with an ESI source and an UPLC AcquityClassic with diode array detector (210 to 400 nm.)

Data are acquired in a full MS scan from m/z 50 to 1000 in positive modewith an acidic elution

The reverse phase separation is carried out at 45° C. on a WatersAcquity UPLC BEH C18 1.7 μm (2.1×50 mm) column for basic elution

Gradient elution is done with:

H2O/ACN/Ammonium_formate (95/5/63 mg/l) +50 μl NH4OH (solvent A)

ACN/H2O/Ammonium_formate (95/5/63 mg/l) +50 μl NH4OH (solvent B).

Acidic gradient program:

HPLC flow rate: 0.6 ml/min to 0.7 ml/min,

injection volume: 1 μl

Full flow in MS.

Flow Time (min) A (%) B (%) (ml/min) 0 99 1 0.4 0.3 99 1 0.4 3.2 0 1000.4 3.25 0 100 0.5 4 0 100 0.5 4.1 99 1 0.4 4.8 90 1 0.4

Method 4 for All Analytical LCMS in Acid Conditions: LCMS Acid:

A QDA Waters simple quadrupole mass spectrometer is used for LC-MSanalysis.

This spectrometer is equipped with an ESI source and an UPLC AcquityHclass with diode array detector (210 to 400 nm).

Data are acquired in a full MS scan from m/z 50 to 1000 in positive modewith an acidic elution.The reverse phase separation is carried out at45° C. on a Waters Acquity UPLC HSS T3 1.8 μm (2.1×50 mm) column foracidic elution

Gradient elution is done with:

Water (solvent A)

Acetonitrile (solvent B)

Water/Acetonitrile/Formic Acid 0.5% (solvent C)

Acidic gradient program:

HPLC flow rate: 0.6 ml/min to 0.7 ml/min, injection volume: 1 μl

Full flow in MS.

Flow Time (min) A (%) B (%) C (%) (ml/min) 0 90 0 10 0.6 0.3 90 0 10 0.63.2 0 90 10 0.6 3.25 0 90 10 0.7 4 0 90 10 0.7 4.1 90 0 10 0.6 5.4 90 010 0.6

Method 5 for All Examples:

Waters Acquity-SQD, Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmcolumn

Mobile phase A: 10 mM Ammonium Formate +0.1% Ammonia

Mobile phase B: 95% MeCN +5% H₂O +0.1% Ammonia

Gradient program (Flow Rate 1.0 mL/min, Column Temperature 40° C.):

Time A % B % 0.00 95 5 0.50 95 5 1.75 5 95 2.00 5 95 2.25 95 5

It will be apparent to the person skilled in the art that differentretention times (RT) may be obtained for LCMS if different analyticalconditions are used.

Additional Analytical HPLC Methods

Method 6

Column: Waters Atlantis dC18 (2.1×100 mm, 3 μm column)

Flow rate: 0.6 mL/min

Solvent A: 0.1% Formic acid/water

Solvent B: 0.1% Formic acid/acetonitrile

Injection Volume: 3 μL

Column temperature: 40° C.

UV Detection wavelength: 215 nm

Eluent: 0 to 5 minutes, constant gradient from 95% solvent A +5% solventB to 100% solvent B; 5 to 5.4 minutes, 100% solvent B; 5.4 to 5.42minutes, constant gradient from 100% solvent B to 95% solvent A +5%solvent B; 5.42 to 7.00 minutes, 95% solvent A +5% solvent B.

Method 7

Column: Waters Atlantis dC18 (2.1×30 mm, 3 μm column)

Flow rate: 1 ml/min

Solvent A: 0.1% Formic acid/water

Solvent B: 0.1% Formic acid/acetonitrile

Injection volume: 34

UV Detection wavelength: 215nm

Eluent: 0 to 1.5 minutes, constant gradient from 95% solvent A +5%solvent B to 100% solvent B; 1.5 to 1.6 minutes, 100% solvent B; 1.60 to1.61 minutes, constant gradient from 100% solvent B to 95% solvent A +5%solvent B; 1.61 to 2.00 minutes, 95% solvent A +5% solvent B.

Method 8

Column: Phenomenex Gemini C18 (2.0 mm×100 mm, 3 μm column)

Flow rate: 0.5 mL/min

Solvent A: 2mM Ammonium bicarbonate/water

Solvent B: Acetonitrile

Injection volume: 3 μL

Column temperature: 50° C.

UV Detection wavelength: 215 nM

Eluent: 0 to 5.5 minutes, constant gradient from 95% solvent A +5%solvent B to 100% solvent B; 5.5 to 5.9 minutes, 100% solvent B; 5.90 to5.92 minutes, constant gradient from 100% solvent B to 95% solvent A +5%solvent B.

Method 9

Column: Phenomenex Gemini C18 (2.0 mm×50 mm, 3 μm column)

Flow rate: 1.0 mL/min

Solvent A: 2mM Ammonium bicarbonate/water

Solvent B: Acetonitrile

Injection volume: 3 μL

Column temperature: 60° C.

UV Detection wavelength: 215 nM

Eluent: 0 to 1.8 minutes, constant gradient from 99% solvent A +1%solvent B to 100% solvent B; 1.8 to 2.1 minutes, 100% solvent B; 2.1 to2.3 minutes, constant gradient from 100% solvent B to 99% solvent A +1%solvent B.

Method 10

Column: Waters XSelect (C18, 50×2.1 mm, 3.5μ)

Flow: 0.8 ml/min Column temp; 35° C.

Eluent A: 0.1% formic acid in acetonitrile

Eluent B: 0.1% formic acid in water

Lin. Gradient: t=0 min 5% A, t=3.5 min 98% A, t=6 min 98% A

Detection: DAD (220-320 nm)

Detection: MSD (ESI pos/neg) mass range: 100-800

Method 11

Column: Waters XSelect (C18, 30×2.1 mm, 3.5 μ)

Flow: 1.0 ml/min Column temp; 35° C.

Eluent A: 0.1% formic acid in acetonitrile

Eluent B: 0.1% formic acid in water

Lin. Gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A

Detection: DAD (220-320 nm)

Detection: MSD (ESI pos/neg) mass range: 100-800

Method 12

Column: Waters XSelect (C18, 30×2.1 mm, 3.5μ)

Flow: 1.0 ml/min Column temp; 35° C.

Eluent A: 0.1% formic acid in acetonitrile

Eluent B: 0.1% formic acid in water

Lin. Gradient: t=0 min 5% A, t=1.6 min 98% A, t=4 min 98% A

Detection: DAD (220-320 nm)

Detection: MSD (ESI pos/neg) mass range: 100-800

Method 13

Column: Waters XSelect (C18, 30×2.1 mm, 3.5μ)

Flow: 1.0 ml/min Column temp; 35° C.

Eluent A: 0.1% formic acid in acetonitrile

Eluent B: 0.1% formic acid in water

Lin. Gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A

Detection: DAD (220-320 nm)

Detection: MSD (ESI pos/neg) mass range: 400-1600Method 14 for thepurification of

Examples 107 to 112

Semi preparative HPLC column: Sunfire prep C18 5 μm 10×150 mm

Isocratic elution: 25% of Solvent A (Water/Acetonitrile/formic acid(v/v/v ; 95/5/0.05)) and 75% Solvent B (acetonitrile/formic acid (v/v ;100/0.075))

Flow rate: 7 mL/min

Method 15 for the analysis of Examples 107 to 112

The LCMS control was performed with a QM Waters triple quadrupole massspectrometer coupled with an HPLC Alliance Waters 2795 quaternary pump.The reverse phase separation is carried out at 45° C. on a WatersSunfire MS C18 column 5 μm (4.6×15 mm) for acidic elution.

Gradient elution is performed with water (Solvent A), acetonitrile(Solvent B) and water/acetonitrile/formic acid (Solvent C v/v/v50/50/5).

Solution pH 3-4, gradient table as below:

Time A % B % C % Flow 0 90 0 10 1.9 1.5 90 0 10 1.9 7.15 2 88 10 2.410.5 2 88 10 2.4 10.6 90 0 10 1.9 13 90 0 10 1.9

Method 16:

Waters UPLC-SQD apparatus; ionization: electrospray in positive and/ornegative mode (ES+/−); chromatographic conditions: column: Acquity CSHC18 1.7 μm -1×30 mm; solvents: A: H₂O (0.1% formic acid) B: CH₃CN (0.1%formic acid); column temperature: 45° C.; flow rate: 0.6 ml/min;gradient (2.0 min): from 5 to 50% of B in 1.0 min; 1.3 min: 100% of B;1.45 min: 100% of B; 1.75 min: 5% of B; retention time=RT (min).

Method 17:

Waters HPLC-ZQ apparatus; ionization: electrospray in positive and/ornegative mode (ES+/−); chromatographic conditions: column: XSelect CSHC18 3.5 μm−3.0×75 mm; solvents: A: H₂O (0.1% formic acid) B: CH₃CN (0.1%formic acid); column temperature: 60° C.; flow rate: 0.8 ml/min;gradient (6.0 min): 6% of B during 0.8 min; From 6% to 100% of B in3.9min; 4.8 min: 100% of B; 5.0 min: 6% of B; 6.0 min: 6% of B;retention time=RT (min).

Method 18:

Waters HPLC-ZQ apparatus; ionization: electrospray in positive and/ornegative mode (ES+/−); chromatographic conditions: column: XSelect CSHC18 3.5 μm—3.0×75 mm; solvents: A: H₂O (0.1% formic acid) B: CH₃CN (0.1%formic acid); column temperature: 60° C.; flow rate: 1.0 ml/min;gradient (7.0 min): 10% of B during 0.2 min; From 10 to 100% of B in 4.3min; 4.85 min: 100% of B; 6.5 min: 10% of B; 7.0 min: 10% of B;retention time=RT (min).

Method 19:

Waters UPLC-SQD apparatus; ionization: electrospray in positive and/ornegative mode (ES+/−); chromatographic conditions: column: Acquity CSHC18 1.7 μm−1×30 mm; solvents: A: H₂O (0.1% formic acid) B: CH₃CN (0.1%formic acid); column temperature: 45° C.; flow rate: 0.6 ml/min;gradient (4.0 min): 5% of B during 0.15 min; 1.3 min: From 5 to 100% ofB in 3.15 min; 3.45 min: 100% of B; 3.85 min: 5% of B; 4.00 min: 5% ofB; retention time=RT (min).

Method 20:

Waters UPLC-SQD apparatus; ionization: electrospray in positive and/ornegative mode (ES+/−); chromatographic conditions: column: Acquity BEHC18 1.7 μm−2.1×50 mm; solvents: A: H₂O (0.1% formic acid) B: CH₃CN (0.1%formic acid); column temperature: 50° C.; flow rate: 0.8 ml/min;gradient (2.5 min): from 5 to 100% of B in 1.8 min; 2.4 min: 100% of B;2.45 min: 100% to 5% of B in 0.05 min; retention time=RT (min).

INTERMEDIATE 1 2-chloro-6-(difluoromethoxy)benzaldehyde

To 2-chloro-6-hydroxy-benzaldehyde (20 g, 128.2 mmol) in MeCN (150 mL)was added an aqueous solution of potassium hydroxide (71.7 g, 1282 mmol)in water (50 mL) at 0° C. and the reaction mixture was stirred at 0° C.for 10 min. Diethyl (bromodifluoro methyl) phosphonate (36.4 mL, 205.1mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for30 min. After completion of reaction (monitored by TLC), the reactionmixture was poured into water (500 mL). The aqueous layer was extractedwith ethyl acetate (1 L X 2). The organic layer was washed with water(500 mL), brine (500 mL) and dried over anhydrous sodium sulphate. Theorganic layer was evaporated under reduced pressure to yield the crudeproduct which was purified by column chromatography (SiO₂, 5% EtOAc inhexane) yielding the title compound (13.9 g, 53% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 10.46 (s, 1H), 7.49 (t, J 8.2 Hz, 1H), 7.37(dd, J 8.1, 1.1 Hz, 1H), 7.20 (m, 1H), 6.61 (t, 1H).

INTERMEDIATE 2N-[[2-chloro-6-(difluoromethoxy)phenyl]methylene]-(S)-2-methyl-propane-2-sulfinamide

To a solution of Intermediate 1 (20 g, 97.08 mmol) in dry THF (100 mL)at 0° C. was added (S)-(−)-t-butyl sulfinamide (12.92 g, 106.79 mmol),K₃PO₄ (61.73 g, 291.2 mmol) and K₂HPO₄ (50.6 g, 291.2 mmol). Then thereaction mixture was stirred at r.t. for 18 h. After completion ofreaction (monitored by TLC), the reaction mixture was filtered throughcelite and washed with ethyl acetate (1 L). The organic layer was washedwith water (500 mL), brine (500 mL) and dried over anhydrous sodiumsulphate. The organic layer was evaporated under reduced pressure andthe residue was purified chromatography (SiO₂, 10% EtOAc in hexane)toafford the title compound (20 g, 87% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 7.45-7.32 (m, 2H), 7.29-7.15 (m,1H), 6.82-6.34 (m, 1H), 1.29 (s, 9H). LCMS (ES+) RT 2.73 min, 309.90(M+H)⁺

INTERMEDIATE 3 Ethyl(3R)-3-[[(5)-tert-butylsulfinyl]amino]-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoate

This procedure used activated zinc and THF dried over sodium andbenzophenone complex. Activated zinc was prepared using the followingprocedure: 150 gof zinc powder was taken in 1N HCl (500 mL), stirred for10 min and decanted. The zinc dust powder was further washed with water(3×500 mL) and decanted. The powder was further washed with acetone(3×500 mL), decanted and dried under vacuum to afford 105 gof activatedzinc.

To activated zinc dust (105 g, 1618 mmol) in dry THF (150 mL) was addedCuCl (19.2 g, 194 mmol) and the reaction mixture was refluxed for 30min. The reaction mixture was cooled to room temperature and ethylbromoacetate (45 mL, 404 mmol in THF 100 mL) was added drop wise. Thereaction mixture was stirred at 50° C. for 30 min. The reaction mixturewas cooled to 0° C. and Intermediate 2 (50 g, 161 mmol in THF 100 mL)was added. The reaction mixture was warmed to r.t. and stirred for 3 h.After completion of reaction (monitored by TLC), the reaction mixturewas filtered through celite and washed with ethyl acetate (700 mL). Theorganic layer was washed with 1N citric acid (500 mL), saturatedsolution of sodium bicarbonate (500 mL), water (500 mL) and brine (500mL).

The organic layer was separated, dried over anhydrous sodium sulphateand evaporated under reduced pressure. The residue was purified bychromatography (SiO₂, 40% EtOAc in hexane) to afford the title compound(59 g, 92% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.29-7.21 (m, 2H), 7.05 (d, J 7.3 Hz, 1H),6.82-6.34 (m, 1H), 5.59 (m, 1H), 4.36 (s, 1H), 4.18-4.02 (m, 2H), 3.25(dd, J 15.6, 7.5 Hz, 1H), 3.01 (dd, J 15.3, 7.5 Hz, 1H), 1.31-1.11 (m,12H).

INTERMEDIATE 4 Ethyl(3R)-3-amino-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoatehydrochloride

To a solution of Intermediate 3 (32 g, 80.6 mmol) in an Ether: EtOH (75mL, 2:1) mixture was added 4M HCl in 1,4-dioxane (70 mL) and thereaction mixture was stirred at r.t. for 1 h. After completion ofreaction (monitored by TLC), the reaction mixture was concentrated underreduced pressure and the residue was washed with diethyl ether (500 mL)to afford the title compound as a yellow solid (22 g, 93% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, J 6.2 Hz, 2H), 7.32-7.10 (m, 3H),6.96 (s, 1H), 5.42 (m, 1H), 4.08 (q, J 7.0 Hz, 2H), 3.36 (dd, J 16.5,7.0 Hz, 1H), 3.14 (dd, J 16.5, 7.8 Hz, 1H), 1.34 (t, J 7.1 Hz, 3H).

INTERMEDIATE 5 Ethyl (3R)-3-(5-bromo-4-fluoro-2-nitro-anilino)-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoate

To a solution of Intermediate 4 (5 g, 17.06 mmol) in MeCN (50 mL) wasadded potassium carbonate (7.06 g, 51.18 mmol) and1-bromo-2,5-difluoro-4-nitrobenzene (4.86 g, 20.47 mmol). The reactionmixture was stirred at 80° C. for 16 h. After completion of reaction(monitored by TLC), the reaction mixture was diluted with ethyl acetate(100 mL) and washed with water (100 mL). The organic layer wasseparated, dried over anhydrous sodium sulphate and concentrated underreduced pressure. The residue was purified by chromatography (SiO₂, 20%EtOAc in hexane) to afford the title compound (6 g, 69% yield) as ayellow viscous liquid.

LCMS (ES+) RT 3.42 min, 510.90/512.90/514.90 (M+H)⁺

INTERMEDIATE 6(3R)-3-(5-bromo-4-fluoro-2-nitro-anilino)-3-[2-chloro-6-(difluoromethoxy)phenyl]propanal

To a solution of Intermediate 5 (6 g, 11.7 mmol) in THF (60 mL) at −78°C. was added DIBAL-H (23 mL, 23.5 mmol) drop wise. The reaction mixturewas stirred for 2 h at −78° C. After completion of reaction (monitoredby TLC), the reaction mixture was quenched with an aqueous solution ofammonium chloride (200 mL). The reaction mixture was diluted with ethylacetate (200 mL) and filtered through celite. The filtrate was washedwith water (200 mL) and the organic layer was separated, dried oversodium sulphate and evaporated under reduced pressure to afford thetitle compound (3 g, 57% yield) as a yellow oil, which was used in thenext step without purification.

INTERMEDIATE 7(4R)-4-(5-bromo-4-fluoro-2-nitro-anilino)-4-[2-chloro-6-(difluoromethoxy)phenyl]-2-trimethylsilyloxy-butanenitrile

To a solution ofIntermediate 6 (3 g, 6.42 mmol) in DCM (50 mL) was addedZnI₂ (0.2 g, 0.64 mmol), TEA (0.09 mL, 0.64 mmol) and TMSCN (1.6 mL,12.84 mmol). The reaction mixture was stirred at r.t. for 3 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasdiluted with water (100 mL) and the organic layer was separated. Theorganic layer was washed with water (100 mL), brine (100 mL), dried overanhydrous sodium sulphate and concentrated under reduced pressure toafford the title compound (3.25 gcrude material) which was used for thenext step without purification.

INTERMEDIATE 8 (1R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

To a solution of Intermediate 7 (3 g, 5.3 mmol) in EtOH (50 mL) wasadded SnCl2 (5 g, 26.46 mmol) and the reaction mixture was heated at 80°C. for 2 h. After completion of reaction (monitored by TLC), thereaction mixture was quenched with water (50 mL) and basified to pH-8using 1N KOH (100 mL). The reaction mixture was diluted with ethylacetate (100 mL) and filtered through celite. The organic layer waswashed with water (100 mL), brine (100 mL), dried over anhydrous sodiumsulphate and concentrated under reduced pressure. The residue waspurified by chromatography (SiO₂, 0-70% EtOAc in hexane) to afford thetitle compound (1.1 g, 47% yield) as a pale brown solid.

¹H NMR (400 MHz, CDCl₃) δ 7.52 (m, 1H), 7.49-7.30 (m, 2H), 7.04-6.67 (m,2H), 6.42 (m, 1H), 6.24-5.91 (m, 1H), 5.79-5.52 (m, 1H), 3.71-3.46 (m,1H), 3.19 (m, 2H).

LCMS (ES+) RT 2.39 min, 447.0/449.0/451.0 (M+H)⁺

INTERMEDIATES 9 AND 10(1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-oland(1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

The title compounds were isolated by chiral purification of Intermediate8 (15μ) under SFC conditions on Chirapak AD (column size: 50*216 mm*mm,flow 360 mL/min, 300 mg/injection/frequency: 8.5 minutes, 25° C.,CO₂+20% MeOH). Chiral analysis was done on Chiralpak AD-H (column size:250*4.6 mm, 5 μm, flow 1 mL/min at 30° C. using 80/20 heptane/ethylacetate containing 0.1%DEA). Under analytical conditions the firsteluting diastereoisomers (5.8 and 9.5 minutes) were a mixture of (1R,3S) and (1R, 3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol.

(1S, 3R) and (1S,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-olwere isolated at 12.5 minutes and 21.5 minutes.

The mixture of a mixture of (1R, 3S) and (1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-olwas separated by chiral separation under SFC conditions on Chiracel OD(column size: 50*266 mm*mm, flow 360 mL/min, 80 mg/injection/frequency:4 minutes, 25° C., CO₂+20% MeOH). Chiral analysis was done on ChiralpakAD-H (column size: 250*4.6 mm, 5 μm, flow 1 mL/min at 30° C. using 70/30heptane/ethyl acetate containing 0.1%DEA). Under analytical conditionsthe first eluting diastereoisomer (4.9 minutes) was the trans isomer,(1R,3 S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol.Combined fractions were evaporated to yield Intermediate 10 (12.7 g,50%). ¹H NMR (400 MHz, CDCl₃) δ 7.41 (m, 3H), 7.23 (d, J 8.0 Hz, 0.4H),6.97 (m, 1.2H), 6.85 (d, J 5.8 Hz, 0.4H), 6.73 (t, J 72.3 Hz, 0.4H),6.41 (m, 1H), 5.95 (dd, J 74.2, 70.8 Hz, 0.6H), 5.71 (m, 0.6H), 5.62 (d,J 7.4 Hz, 0.4H), 3.22 (m, 2H). as a mixture of rotamers 6/4. LCMS basic(ES⁺) 2.50 min., 446.96/448.95/450.95 (M+H)⁺.

Under analytical conditions the second eluting diastereoisomer (6.6minutes) was the cis isomer,(1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol.Combined fractions were evaporated to yield Intermediate 9 (6.6 g, 26%).¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J 8.5 Hz, 1H), 7.31 (m, 1.8H), 7.20(m, 0.6H), 7.08 (d, J 7.9 Hz, 0.6H), 6.88 (d, J 5.5 Hz, 0.6H), 6.74 (d,J 5.2 Hz, 0.4H), 6.61 (t, J 72.5 Hz, 0.4H), 6.15 (t, J 72.0 Hz, 0.6H),6.08 (m, 1H), 5.63 (m, 1H), 3.56 (m, 0.6H), 3.43 (m, 0.4H), 2.98 (m,0.4H), 2.80 (m, 0.6H),as a mixture of rotamers 6/4. LCMS acid (ES⁺) 2.20min, 446.96/448.95/450.91 (M+H)⁺.

Under preparative conditions the order of elution was reversed.

INTERMEDIATE 10(1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

The title compound can also be prepared by the following procedure:Intermediate 9 (3.65 g, 8.146 mmol, 1 eq) and triphenylphosphine (2.62g, 9.775 mmol, 1.2 eq) were solubilized in 8 mL of dry THF, under aninert atmosphere of nitrogen. Acetic acid (513 μL, 8.960 mmol, 1.1 eq)was added and the mixture cooled to 0° C. A solution of DIAD (2.42 mL,12.220 mmol, 1.5 eq) in 8 mL of dry THF was added drop wise. Thereaction was slowly warmed to r.t. and the reaction continued for 2hours at this temperature. 20 mL of ethyl acetate were added to thereaction mixture before washing with 3×10 mL of a saturated solution ofNaHCO₃. The organic layer was dried over anhydrous magnesium sulfate andconcentrated under vacuum. The residue was purified by chromatography(SiO₂, 5% MeOH in DCM) giving 4.8 g(94% yield) of the inverted acetateintermediate which was used directly used in the next step.[1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]acetate(4.8 g, 9.800 mmol, 1 eq) was solubilized in 48 mL of methanol.Potassium carbonate (1.4 g, 9.800 mmol, 1 eq) was added and the reactioncontinued for 1 hour at r.t. The reaction was evaporated and the residuewas taken up in ethyl acetate (50 mL) and water (20 mL). The organiclayer was washed by water (2×20 mL), dried over sodium sulfate, filteredand concentrated under vacuum to give 4.7 gof the crude title compoundas a slightly beige solid.

INTERMEDIATE 11 tert-butyl-dimethyl-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaboro lan-2-yl)pyrimidin-2-yl]ethoxy]silane

2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (10g, 37.8601 mmol), tert-butyldimethylchlorosilane (11.76 g, 75.72 mmol)and imidazole (7.890 g, 115.89 mmol) were dissolved in anhydrous DMF(150 mL). The reaction was stirred at 85° C. for 4 days. EtOAc (100 mL)and water (250 mL) were added, the aqueous layer was extracted with 3×20mL of EtOAc then the combined organic layers were washed with brine(3×20 mL). and dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography (SiO₂, 0-100% EtOAc in heptane)to afford the title compound as a transparent oil (12.0 g, 83.76%). ¹HNMR (400 MHz, CDCl₃) δ 9.04 (s, 2H), 1.70 (s, 6H), 1.40 (s, 12H), 0.94(s, 9H), 0.01 (s, 6H). LCMS acid (ES⁺) RT 3.04min, 297.20 (M+H)⁺.

INTERMEDIATE 12 (1R,3S)-7-[2-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

Intermediate 10 (5.12 g, 11.44 mmol,), Intermediate 11 (5.19 g, 13.73mmol) and cesium carbonate (5.59 g, 17.16 mmol, 1.5 eq) were placed in atube, and filled with argon. Degassed 1,4-dioxane (41.2 mL, 3.6 mL/mmol)and degassed water (4.1 mL, 0.36 mL/mmol) were added and the resultingslurry was stirred at r.t. for 5 minutes before addition of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (418.7 mg,

0.572 mmol, 0.05 eq). The reaction mixture was placed on a pre-heatedstirring plate at 90° C. and stirred at this temperature for 2 h.Reaction mixture was cooled down to r.t. before addition of 50 mL ofethyl acetate and 50 mL of water. The aqueous layer extracted with 3×20mL of ethyl acetate. Combined organic layers were dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure.

The crude was purified by chromatography (SiO₂, 30-100% EtOAc inheptane) to afford the title compound (3.8 g, 53% yield).

LCMS basic (ES⁺) RT 3.54min., 619.20/621.16 (M+H)⁺.

INTERMEDIATE 13(1R,3R)-7-[2-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazo1-3-amine

Intermediate 12 (3.369 g, 5.441 mmol) was suspended in 11 mL of drytoluene. At 0° C., diphenylphosphoryl azide (1.58 mL, 7.071 mmol) wasadded followed by addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.139mL, 7.616 mmol). The reaction was allowed to reach r.t. and stirred atthis temperature for 2 h then heated at 50° C. for 18 h.

The reaction mixture was diluted by 100 mL of water and 100 mL of ethylacetate. The aqueous layer was extracted by ethyl acetate (3×20 mL).Combined organic layers were washed with successivelly 20 mL of asaturated solution of NH₄Cl and 20 mL of a saturated solution of NaHCO₃,dried over anhydrous magnesium sulfate and concentrated in vacuum.

The crude azide intermediate was solubilized in a solution oftetrahydrofuran (50 mL, 10 mL/mmol) and water (5 mL, 1 mL/mmol) beforeaddition of 1 M solution of trimethylphosphine in toluene (11 mL, 11mmol). The reaction mixture was stirred at r.t. for 2 h. Solvents wereevaporated and the residue was purified by chromatography (SiO₂, 5-8%MeOH in DCM) to afford the title compound (2.8 g, 83% yield).

LCMS basic (ES⁺) RT=3.52min., 618.20/620.20 (M+H)⁺.

INTERMEDIATE 14(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 13 (2.78 g, 4.50 mmol, 1 eq), sodium carbonate (2.38 g,22.5 mmol, 5 eq) and dichlorobis(dicyclohexylphosphino)propane]palladium(II) [Pd-133 from JohnsonMatthey](552 mg, 0.899 mmol, 0.2 eq) were solubilized/suspended indegassed (nitrogen) 1,4-dioxane (54 mL, 12 mL/mmol). The reactionmixture was heated overnight at 150° C. under 5 atmosphere of CO gas.The reaction mixture was filtered over celite, which was thoroughlywashed with ethanol. Solvents were evaporated and the residue waspurified by chromatography (SiO₂, 80-100% EtOAc in heptane), giving thetitle compound (1.39 g, 50% yield).

LCMS basic (ES⁺) RT 3.47 min., 610.25/611.25 (M+H)⁺

INTERMEDIATE 15 ethyl(3R)-3-(5-bromo-2-nitro-anilino)-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoate

Intermediate/5 was prepared, using the same procedure described forpreparation of Intermediate 5, from Intermediate 4 (9.3 g, 28.3 mmol)and 4-bromo-2-fluoro-nitrobenzene (7.4 g, 34 mmol). The reaction wasstirred overnight at 80° C. and purified by chromatography (SiO₂, 10%EtOAc in hexane). Intermediate/5 was obtained as a yellow oil (12.5 g,90% yield).

LCMS (ES⁺) 495 (M+H)⁺

INTERMEDIATE 16 (3R)-3-(5-bromo -2-nitro-anilino)-3-[2-chloro-6-(difluoromethoxy)phenyl]propanal

Intermediate 16 was prepared from Intermediate/5 (12.5 g, 25.4 mmol)using the same procedure described for preparation of Intermediate 6.Following work-up the crude Intermediate 16 was purified bychromatography (SiO₂, 15% EtOAc in hexane) yielding Intermediate 16 (9g, 80% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 9.80 (d, J 1.3 Hz, 1H), 8.78 (d, J 9.0 Hz,1H), 7.99 (d, J 9.0 Hz, 1H), 7.27 (d, J 3.2 Hz, 2H), 7.21-7.08 (m, 1H),6.81-6.66 (m, 2H), 5.93 (m,1H), 3.56-3.38 (m, 2H), 3.12 (dd, J 17.9, 5.2Hz, 1H).

INTERMEDIATE 17(4R)-4-(5-bromo-2-nitro-anilino)-4-[2-chloro-6-(difluoromethoxy)phenyl]-2-trimethylsilyloxy-butanenitrile

Intermediate 17 was prepared from Intermediate 16 (9 g, 20 mmol) usingthe same procedure described for preparation of Intermediate 7. Thereaction was stirred at r.t. for 2 h. After completion of reaction(monitored by TLC), water (200 mL) was added and extracted with DCM (500mL). After evaporation of organic layer, the crude product, obtained asa yellow oil (9μ), was used directly for the next step without anypurification.

INTERMEDIATE 18 (1R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

Intermediate 18 was prepared from Intermediate 17 (9 g, 16.4 mmol) usingthe same procedure described for preparation of Intermediate 8. Thecrude product was purified by chromatography (SiO₂, 60% EtOAc in hexane)then triturated with hexane:ethyl acetate to yield the title compound (3g, 43% yield) as a yellow solid.

LCMS (ES⁺) 431 (M+H)⁺

INTERMEDIATE 19 AND 20(1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-oland(1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

The title compounds were isolated by chiral purification of Intermediate18 (12.5μ) by 2 successive chiral separation.

First chiral separation:

Under SFC conditions on Chiracel OD (column size: 50*266 mm*mm, flow 360mL/min, 20 mg/injection/frequency: 4 minutes, 25° C., CO₂+20% MeOH).Chiral analysis was done on Chiralcel OD-H (column size: 250*4.6 mm,flow 1 mL/min at 30° C. using 100% methanol containing 0.1%DEA). Underanalytical conditions the first eluting diastereoisomer (3.9 minutes)was either (1S, 3R) or (1S, 3S)7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol.The second eluting diastereoisomers (4.7 minutes) were a mixture of (1R,3S) along with either (1S, 3R) or (1S, 3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-oland the third eluting diastereoisomer (5.4 minutes) was (1R, 3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol.Combined fractions of the third eluting diastereomer were evaporated toyield to Intermediate 19 (3.63 g, 29%). ¹H NMR (400 MHz, DMSO) δ 7.57(m, 2.3H), 7.45 (m, 0.8H), 7.35 (d, J 8.0 Hz, 0.6H), 7.26 (m, 1H), 7.17(m, 0.3H), 6.83 (t, J72.5 Hz, 1H), 6.69 (bs, 1H), 6.15 (m, 1H), 6.07 (m,1H), 5.38 (m, 1H), 3.38 (m, 1H), 2.67 (m, 1H) as a mixture of rotamers7/3. LCMS acid (ES⁺) RT 4.31 min., 429.10/431.08/433.05 (M+H)⁺.

Second chiral separation:

Under SFC conditions on Whelko 01 (R,R) (column size: 50*227 mm*mm, flow360 mL/min, 690 mg/injection/frequency: 5.5 minutes, 25° C., CO₂+20%EtOH). Chiral analysis was done on Chiralcel OD-H (column size: 250*4.6mm, flow 1 mL/min at 30° C. using 50/50 heptane/isopropyl alcoholcontaining 0.1%DEA). Under analytical conditions, the first elutingdiastereomer (4.1 minutes) was either (1S, 3R) or (1S, 3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol.

Under analytical conditions, the second eluting diastereomer (5.9minutes) was the trans isomer, (1R,3 S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazo1-3-o 1. Combined fractions were evaporated to yield Intermediate 20(4.46 g, 36%).¹H NMR (400 MHz, DMSO) δ 7.55 (m, 3.4H), 7.31 (m, 1.4H),7.12 (d, J 7.8 Hz, 0.6H), 7.03 (t, J 73.0 Hz, 0.6H), 6.89 (s, 0.6H),6.81 (s, 0.4H), 6.32 (dd, J 8.4, 5.9 Hz, 1H), 6.10 (d, J 6.6 Hz, 1H),5.32 (m, 0.6H), 5.26 (t, J 6.9 Hz, 0.4 H), 3.13 (m, 1H), 2.93 (m, 1H).as a mixture of rotamers 6/4. LCMS acid (ES⁺) RT 4.40 min.,429.05/431.08/433.05 (M+H)⁺.

Under preparative conditions the order of elution was reversed.

INTERMEDIATE 20 (1R,3 S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

The title compound was prepared from the same procedure as thepreparation of Intermediate 10 starting from Intermediate 19 (3.63 g,8.450 mmol), triphenylphosphine (2,66 g, 10.14 mmol), and acetic acid(0.5 mL, 9.295 mmol) THF (34 mL),DIAD (2.62 mL, 12.67 mmol) in 5 ml ofdry THF giving 3.6 g(91%) of the inverted acetate intermediate which wasused directly in the next step. Using the following conditions. [(1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2a]benzimidazol-3-yl]acetate(4.0 g, 8.480 mmol) was solubilized in 40 mL of methanol. Potassiumcarbonate (1.1 g, 8.48 mmol, 1 eq) was added and the reaction continuedfor 1 hour at rt. The methanol was evaporated and the residue was takenup in ethyl acetate (50 mL) and water (20 mL). The organic layer waswashed by water (2×20 mL), dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to give 4.9 gof crude title compound as abrown oil use without further purification. LCMS basic (ES⁺) RT 2.46min., 428.94/430.96/433.16 (M+H)⁺.

INTERMEDIATE 21(1R,3S)-7-[2-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

Intermediate 20 (4.46 g, 10.38 mmol), Intermediate 11 (3.92 g, 10.38mmol) following the protocol described for intermediate 12 using cesiumcarbonate (5.07 g, 15.57 mmol), 1,4-dioxane (37.1 mL, 3.6 mL/mmol),water (3.7 mL, 0.36 mL/mmol),[1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II) (379.8 mg,0.5191 mmol, 0.05 eq), The crude was purified by chromatography (SiO₂,30-100% EtOAc in hexane) to yield the title compound (5.7 g, 92% yield).

LCMS acid (ES⁺) RT 3.64 min., 601.29/603.21 (M+H)⁺

INTERMEDIATE 22(1R,3R)-7-[2-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

Intermediate 22 was prepared from Intermediate 21 following the protocoldescribed for intermediate 13, using toluene (34 mL), diphenylphosphorylazide (5.0 mL, 24.22 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (3.62 mL,24.22 mmol) for the first step and tetrahydrofuran (172 mL), water (17mL), 1 M solution of trimethylphosphine in toluene (34.6 mL, 20.8 mmol)for the second step.

The crude residue was purified by chromatography (SiO₂, 0-5% MeOH inDCM, 1% NH₄) to afford the title compound (7 g, 61% yield).

LCMS basic (ES⁺) RT 3.49min., 600.25/602.25 (M+H)⁺

INTERMEDIATE 23(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 23 was prepared from Intermediate 22 (7.00 g, 7.931 mmol)following the protocol described for Intermediate 14 using sodiumcarbonate (6.181 g, 58.31 mmol), dichlorobis(dicyclohexylphosphino)propane]palladium(II) [Pd-133 from JohnsonMatthey](1.43 g, 0.254 mmol), 1,4-dioxane (95 mL, 12 mL/mmol) and 5atmosphere of CO gas.

The crude was purified by chromatography (SiO₂, 50-100% EtOAc inheptane) to afford the title compound (3.2 g, 62% yield) as a whitesolid.

¹H NMR (400 MHz, DMSO) δ 9.23 (d, J 6.8 Hz, 1H), 9.16 (s, 2H), 8.32 (dd,J 5.9, 3.5 Hz, 1H), 7.88 (dd, J51.9, 43.2 Hz, 1H), 7.84 (s, 1H), 7.71(dd, J 8.3, 1.8 Hz, 1H), 7.60 (m, 3H), 6.47 (d, J 7.1 Hz, 1H), 4.99 (t,J 6.8 Hz, 1H), 3.58 (m, 1H), 2.85 (d, J 13.4 Hz, 1H), 1.76 (s, 6H), 0.95(s, 9H), 0.01 (s, 6H). LCMS basic (ES⁺) RT 3.43 min., 592.27 (M+H)⁺.

INTERMEDIATE 24(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 23 (1.0 g, 1.690 mmol) was dissolved in dry THF (10 mL/g)and tetrabutylammonium iodate (0.250 g, 0.676 mmol) was added. At 0° C.,sodium hydride (60% in mineral oil) (0.081 g, 2.028 mmol) was added andthe reaction mixture was stirred at r.t. for 35 minutes. Iodomethane(0.727 g, 5.070 mmol) was added and the reaction mixture was stirred atr.t. for 18 h. Distilled water (200 mL) was added, the mixture wasextracted by of ethyl acetate (3×150 mL). Combined organic layers weredried over anhydrous magnesium sulfate and concentrated in vacuo. Theresidue was purified by chromatography (SiO₂, 50-100% EtOAc in heptane)to afford the title compound (0.868 g, 85% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 2H), 8.54 (d, 8.2 Hz, 1H), 7.93 (d, J8.5 Hz, 1 H), 7.80 (s, 1H), 7.59 (d, J 8.5 Hz, 1H), 7.49 (t, J 8.2 Hz,1H), 7.37 (d, J 8.2 Hz, 1H), 6.89 (t, J 72.5 Hz, 1H), 6.42 (d, J 6.9 Hz,1H), 5.30 (d, J 6.7 Hz, 1H), 3.63 (m, 4H), 2.99 (d, J 13.6 Hz, 1H), 1.75(s, 6H), 0.92 (s, 9H), 0.00 (s, 6H). LCMS basic (ES⁺) RT 3.51 min.,606.25 (M+H)⁺

INTERMEDIATE 25(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-ethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 23 (0.075 g, 0.127 mmol, 1 eq) was dissolved in dry THF (10mL). At 0° C., sodium hydride (60% in mineral oil) (0.008 g, 0.190 mmol)was added and the reaction mixture was heated at 65° C. for 2.5 h, thenwas allowed to reach r.t. and iodoethane (0.059 g, 0.380 mmol) wasadded. The reaction mixture was then stirred at r.t. for 60 h.Additional Iodoethane (50 μL) was added and the reaction mixture wasstirred at r.t. for 2 h. Distilled water (20 mL) was added, the mixturewas extracted with 3×20 mL of ethyl acetate. Combined organic layerswere dried over anhydrous magnesium sulfate and concentrated invacuum.The residue was purified by chromatography (SiO₂, 50-100% EtOAcin heptane) to afford the title compound as a white solid (0.069 g, 88%yield). LCMS basic (ES⁺) RT 2.24 min. 506.23 (M+H)⁺.

INTERMEDIATE 26(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-(propan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

A solution of Intermediate 23 (25 mg, 0.0423 mmoL), potassium hydroxide(2.85 mg, 0.0507 mmoL), tetrabutylammonium bromide (12.26 mg, 0.0380mmoL) and 2-iodopropane (14.36 mg, 0.0845 mmoL) in dry THF (0.8 mL) wasstirred at r.t. for 24 h. The reaction mixture was quenched with waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulphate and concentrated todryness to afford the title compound (10 mg) which was used in the nextstep without further purification.

LCMS basic (ES⁺) RT 3.60 min. 534.30 (M+H)⁺.

INTERMEDIATE 27(1R,3S)-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

Intermediate 27 was prepared from Intermediate 20 (4.61 g, 10.30 mmol),following the protocol described for Intermediate 12, using2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(3.00 g, 11.330 mmol), cesium carbonate (5.03 g, 15.450 mmol),1,4-dioxane (37.1 mL), water (3.7 mL),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (376.8 mg,0.5150 mmol). The crude was purified by chromatography (SiO₂, 30-100%EtOAc in heptane) to afford the title compound (3.6 g, 69%).

¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1.2H), 8.73 (s, 0.8H), 7.59 (d,J=11.0 Hz, 1H), 7.37 (m, 2.8H), 7.23 (m, 0.6H), 6.99 (d, J=8.2 Hz,0.6H), 6.84 (d, J=6.5 Hz, 0.6H), 6.74 (t, J=72.5 Hz, 0.6H), 6.70 (d,J=6.5 Hz, 0.4H), 6.51 (m, 1H), 6.02 (dd, J1=74.0 Hz, J2=71.0 Hz, 0.4H),5.77 (dd, J1=7.8 Hz, J2=3.3 Hz, 0.6H), 5.68 (d, J=7.1 Hz, 0.4H), 4.60(bs, 1H), 3.27 (m, 2H), 1.64 (s, 3.60H), 1.62 (s, 2.40). LCMS acid (ES⁺)RT 1.91 min. 505.15/507.15 (M+H)⁺.

INTERMEDIATE 28 Butyl3-(difluoromethoxy)-2-[(1R,3S)-6-fluoro-3-hydroxy-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]benzoate

A solution of Intermediate 27 (900 mg, 1.783 mmoL), sodium carbonate(944 mg, 8.913 mmoL), dichloro[bis(dicyclohexylphosphino)propane]palladium(II) (54.7 mg, 0.08913 mmol)in 10 mL of 1-butanol was heated for 16 h at 150° C. under 4 atm of COgas.

The reaction mixture was concentrated in vacuo, the residue was taken upin 50 mL of ethyl acetate and washed with 3×20 mL of NaOH 0.1 M. Theorganic layer was dried over anhydrous sodium sulphate and concentratedin vacuo. The crude material was purified by chromatography (SiO₂, 80%EtOAc in hexane), to afford the title compound (490 mg, 48.2% yield).

LCMS acid (ES⁺) RT 2.66 min. 571.25 (M+H)⁺.

INTERMEDIATE 293-(difluoromethoxy)-2-[(1R,3S)-6-fluoro-3-hydroxy-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]benzoicacid

Intermediate 28 (470 mg, 0.8237 mmoL) was dissolved in 4.7 mL ofmethanol. A 5 N solution of sodium hydroxide (0.3295 mL, 1.647 mmol) wasadded and the mixture was stirred at room temperature for 48 h. Thereaction mixture was neutralized with HC1 1N and the solvent wasevaporated. The aqueous phase was extracted with ethyl acetate (3×25mL), the combined organic layers were dried over magnesium sulphate andconcentrated in vacuo to afford crude 511 mg of the title compound usedwithout further purification.

LCMS acid (ES⁺) RT 2.05 min., 515.17 (M+H)⁺.

INTERMEDIATE 30 Ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate

The title compound was prepared according to the procedure provided ininternational patent application WO 2014/009295 .

INTERMEDIATE 313-(6-bromo-2-ethoxycarbonyl-imidazo[1,2-a]pyridin-3-yl)-3-(2-chlorophenyl)propanoicacid

Intermediate 30 (8 g, 29.73 mmol), 2-chlorobenzaldehyde (6.7 ml, 59.58mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (8.6 g, 59.67 mmol), L-proline(170 mg, 1.48 mmol) and MgSO₄ (11 g, 91.39 mmol) in acetonitrile (80 mL)was heated at 90° C. for 33 h, followed by 100° C. 15 h. The reactioncooled to r.t., and the solid filtered off, and washed with methanol(2×50 mL). The filtrate was concentrated in vacuo and triturated withdiethyl ether (50 mL) and sonicated for 10min and resulting gum wasfiltered off and rinsed with diethyl ether (2×50 mL) yielding the titlecompound as beige solid (10.2 g, 76%). ¹H NMR (500 MHz, Methanol-d₄) δ8.79 (s, 1H), 7.74 (d, J 7.7 Hz, 1H), 7.67-7.55 (m, 2H), 7.43-7.34 (m,2H), 7.34-7.20 (m, 1H), 5.56 (dd, J 9.5, 6.0 Hz, 1H), 4.35 (qt, J 7.4,3.7 Hz, 2H), 3.70 (dd, J 16.7, 9.5 Hz, 1H), 3.40 (dd, J 16.7, 6.0 Hz,1H), 1.34 (t, J 7.1 Hz, 3H). LCMS (ES⁺) RT 1.24 min, 451.0/453.0 (M+H)+.

INTERMEDIATE 32 Ethyl6-bromo-3-[1-(2-chlorophenyl)-3-ethoxy-3-oxo-propyl]imidazo[1,2-a]pyridine-2-carboxylate

Thionyl chloride (4 ml, 55.14 mmol) was added to the stirred solution ofIntermediate 31 (10.2 g, 20.1 mmol) in EtOH (100 mL) at 0° C. Thereaction mixture warmed to r.t. and stirred for 20 h. The reactionmixture was concentrated in vacuo and resulting residue was trituratedwith EtOAc (100 mL) and washed with sat. NaHCO₃ (100 mL) and furtherextracted with EtOAc (2×50 mL). The combined organic layers were washedwith water (50 mL), brine (50 mL), dried over sodium sulfate, filteredand concentrated in vacuo. The residue was purified by chromatography(SiO₂, 0-100% EtOAc in heptane) yielding the title compound as an orangegum (8.2 g, 85%). ¹H NMR (500 MHz, CDCl₃) δ 8.40 (s, 1H), 7.65 (dd, J7.8, 1.5 Hz, 1H), 7.55 (d, J 9.5 Hz, 1H), 7.34 (dd, J 7.9, 1.4 Hz, 1H),7.28 (dd, J9.5, 1.8 Hz, 1H), 7.27-7.23 (m, 1H), 7.20 (td, J 7.6, 1.6Hz,1H), 5.44 (dd, J9.8, 5.6 Hz, 1H), 4.42 (q, J 7.1 Hz, 2H), 4.09-3.94(m, 2H), 3.82 (dd, J 16.6, 9.9 Hz, 1H), 3.26 (dd, J 16.6, 5.5 Hz, 1H),1.40 (t, J 7.1 Hz, 3H), 1.12 (t, J7.1 Hz, 3H). LCMS (ES⁺) RT 1.44 min,479.0/481.0 (M+H)⁺.

INTERMEDIATE 33 Ethyl7-bromo-1-(2-chlorophenyl)-3-oxo-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridine-2-carboxylate

Intermediate 32 (4 g, 8.34 mmol) was co-evaporated twice with toluene(50 mL) and the residue dissolved in dry toluene (400 mL) and degassedwith N₂(g) for 5 min. The mixture was cooled to −10° C. (external temp)and a 25% w/w solution of potassium 2-methylbutan-2-olate in toluene(7.5 mL, 13.37 mmol) was then added drop wise and stirred for 30min at−10° C. The reaction mixture was quenched with acetic acid (2 mL) anddiluted with water (200 mL), extracted with EtOAc (2×200 mL). Thecombined organic layer was washed with sat. aq. sodium bicarbonate (100mL), brine (100 mL), dried over sodium sulfate, filtered andconcentrated in vacuo yielding the title compound as a pale yellow solid(3.3 g, 82%). ¹H NMR (500 MHz, CDCl₃) δ 7.77 (s, 1H), 7.65 (d, J 9.8 Hz,1H), 7.52 (d, J 6.7 Hz, 1H), 7.40 (dd, J 9.8, 1.5 Hz, 1H), 7.32 (t, J8.3 Hz, 1H), 7.25-7.15 (m, 1H), 6.67 (s, 1H), 5.59 (s, 1H), 4.30 (q, J7.1 Hz, 2H), 3.89 (s, 1H), 1.33 (t, J 7.1 Hz, 3H). LCMS (ES⁺) RT 1.35min, 433.0/435.0 (M+H)⁺.

INTERMEDIATE 347-bromo-1-(2-chlorophenyl)-1,2-dihydro-3H-cyclopenta[4,5]imidazo[1,2-a]pyridin-3-one

Intermediate 33 (3.2 g, 6.64 mmol) was dissolved in DMSO (50 mL) andwater (10 mL) then heated at 100° C. for 48 h. The reaction was cooledto r.t. and poured on to ice and left to stand for lh. The resultingresidue was filtered off and washed with water yielding the titlecompound as a pale yellow solid (2.5 g, 99%). ¹H NMR (500 MHz, CDCl₃) δ7.81 (s, 1H), 7.65 (dd, J 9.8, 0.8 Hz, 1H), 7.52 (d, J 8.0 Hz, 1H), 7.38(dd, J 9.8, 1.8 Hz, 1H), 7.29 (td, J 7.8, 1.6 Hz, 1H), 7.21 (t, J 7.4Hz, 1H), 6.77 (s, 1H), 5.22 (s,1H), 3.73 (dd, J 18.4, 7.1 Hz, 1H), 2.92(d, J 19.0 Hz, 1H). LCMS (ES⁺) RT 1.27 min, 361.0/363.0 (M+H)⁺.

INTERMEDIATE 351-(2-chlorophenyl)-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-1,2-dihydro-3H-cyclopenta[4,5]imidazo[1,2-a]pyridin-3-one

Intermediate 34 (1 g, 2.65 mmol),2-[5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(0.84 g, 3.19 mmol) were dissolved in dioxane (40 mL) then 2M disodiumcarbonate (4 mL) was added and the mixture was degassed with N₂ for 5min. Bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron;dichloromethane; dichloropalladium (108 mg, 0.13 mmol) was added and thereaction was heated to 80° C. for 1.5 hours. The reaction mixture wasthen cooled to r.t. and diluted with water (50 mL) and extracted withEtOAc (3×50 mL). The combined organic layers were washed with brine (50mL), dried over sodium sulfate, filtered, concentrated in vacuo. Theresidue was purified by chromatography, (SiO₂, 10-100% EtOAc in heptane)yielding the title compound as a light brown solid (1.1 g, 96%). ¹H NMR(500 MHz, CDCl₃) δ 8.81 (s, 2H), 7.91 (d, J 9.6 Hz, 1H), 7.87 (s, 1H),7.53 (dd, J 9.5, 1.6 Hz, 2H), 7.29 (td, J 7.8, 1.5 Hz, 1H), 7.21 (t, J7.4 Hz, 1H), 6.84 (s, 1H), 5.31 (s, 1H), 4.45 (s, 1H),3.77 (dd, J 18.3,7.0 Hz, 1H), 2.99 (d, J 18.9 Hz, 1H), 1.63 (s, 6H). LCMS (ES⁺) RT 1.14min, 419.0/421.0 (M+H)⁺.

INTERMEDIATE 362-{5-[(1-(2-chlorophenyl)-3-(methoxyimino)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl]pyrimidin-2-yl}propan-2-ol

Intermediate 35 (500 mg, 1.11 mmol), 0-methylhydroxylamine hydrochloride(185 mg, 2.22 mmol) and sodium acetate (182 mg, 2.22 mmol) in ethanol(20 mL) were heated at 85° C. for 6 h. The reaction mixture was cooledto r.t. , concentrated in vacuo then diluted with sat. aq. sodiumbicarbonate (50 mL) and extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine (25 mL), dried over sodiumsulfate, filtered, concentrated in vacuo yielding the title compound asbeige solid (500 mg, 95%).

¹H NMR (500 MHz, CDCl₃) δ 8.80 (d, J 1.1 Hz, 2H), 7.98-7.73 (m, 2H),7.54-7.36 (m, 2H), 7.26 (s, 2H), 6.94-6.64 (m, 1H), 5.31-5.09 (m, 1H),4.48 (d, J 9.5 Hz, 1H), 4.07 (d, J 53.7 Hz, 3H), 3.97(dd, J 18.2, 7.9Hz, 1H), 3.23-3.10 (m, 1H), 1.56 (s, 6H).

LCMS (ES⁺) RT 1.17 and 1.29 min, 448.0/450.0 (M+H)⁺.

INTERMEDIATE 372-{5-[3-amino-1-(2-chlorophenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl]pyrimidin-2-yl}propan-2-ol

A solution of Intermediate 36 (500 mg, 1.12 mmol), 7M ammonia in MeOH(0.64 mL) in methanol (50 mL) was passed over a Raney Nickel cartridgeat a flow-rate of 1 ml/min, 60 bar hydrogen pressure at 80° C. in aH-Cube® continuous-flow hydrogenation reactor. This process was repeatedthree times and mixture was concentrated in vacuo. The residue waspurified by preparative HPLC yielding the title compound as an off whitesolid (300 mg, 64%). A 1.6:1 cis/trans mixture of distereosiomers wasisolated. ¹H NMR, cis distereoisomer, (500 MHz, CDCl₃) δ 8.78 (s, 2H),7.74 (d, J 20.0 Hz, 2H), 7.51-7.44 (m, 1H), 7.40-7.33 (m, 1H), 7.24-7.17(m, 2H), 7.14 (t, J 7.5 Hz, 1H), 7.00 (dd, J 7.6, 1.6 Hz, 1H), 4.96 (dd,J 8.1,6.0 Hz, 1H), 4.59 (dd, J 7.4, 5.7 Hz, 3H), 3.69 (dt, J 13.5, 8.1Hz, 1H), 2.11 (dt, J 13.4, 5.6 Hz, 1H), 1.61 (s, 6H). LCMS (ES⁺) RT1.60min (cis) and 1.65 min (trans), 420.0/422.0 (M+H)⁺.

INTERMEDIATE 38

(1R,3S)-7-chloro-1-[2-bromo-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

The title compound was prepared in a sequence of steps analogous tothose described for Intermediate 10 starting from2-bromo-6-hydroxy-benzaldehyde and utilising4-chloro-2-fluoro-nitrobenzene instead of1-bromo-2,5-difluoro-4-nitrobenzene in the fifth synthetic step.

INTERMEDIATE 39

(1R,3S)-7-chloro-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

The title compound was prepared in a sequence of steps analogous tothose described for Intermediate 10 starting from2-bromo-6-hydroxy-benzaldehyde and utilising1-chloro-2,5-difluoro-4-nitrobenzene, instead of1-bromo-2,5-difluoro-4-nitrobenzene in the fifth synthetic step.

INTERMEDIATE 40

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

Intermediate 38 (5 g, 11.64 mmol) was suspended in toluene (22 mL) andcooled to 0° C. before addition of diphenylphosphoryl azide (3.4 mL, 15mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 mL, 16 mmol). Themixture was allowed to warm up to r.t and stirred for 2 hours andsubsequently at 45° C. overnight. The reaction mixture was diluted withEtOAc (150 mL) and the organic phase washed with a saturated aqueoussolution of ammonium chloride (50 mL) then a saturated solution ofaqueous sodium bicarbonate (50 mL), and concentrated in vacuo. The cruderesidue thus obtained was solubilized in THF (100 mL) and water (10 mL),trimethylphosphine (17.46 mL, 17.46 mmol) was added and the reactionmixture stirred overnight. The mixture was concentrated in vacuo,partitioned between EtOAc (200 mL) and water (150 mL). The organic layerwas extracted with 0.2M HCl aq (3×200 mL). The combined acid layer wasstirred in an ice bath, whilst 10% NaOH solution was added with stirringuntil pH increased to 10. The stirred was continued for further 15minutes to complete precipitation. The precipitate was filtered, rinsedwith water (20 mL), then dried under suction for 10 minutes beforedrying under high vacuum overnight to afford 3.92 g(78%) of the titlecompound as an off white solid. LCMS basic: RT 1.96 min. (ES+) 428/430(M+H)⁺

INTERMEDIATE 41

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

The title compound was prepared from Intermediate 39 using theexperimental protocol described for the preparation of Intermediate 40.The crude material was purified by column chromatography over silica gelusing EtOAc/MeOH (100/0 to 70/30) as eluent, yielding 15 g(83%) of thetitle compound as an amorphous solid. LCMS basic: RT 2.04 min. (ES+)446/448 (M+H)⁺.

INTERMEDIATE 42

tert-butyl{(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

To a solution of Intermediate 40 (700 mg, 2 mmol) in DCM (10 mL), at 0°C., was added dropwise triethylamine (500 μL, 4 mmol) and di-tert-butyldicarbamate (400 mg, 2 mmol) portionwise. The reaction was stirred at 0°C. for 1 hour and at r.t. overnight. The reaction mixture was pouredinto ice-water (20 mL) and the aqueous layer was extracted by DCM (3×10mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyover silica gel (heptane/EtOAc 2/8), yielding 626 mg (70%) of the titlecompound. LCMS basic (ES+) RT 2.92 min., 528.0/530.0 (M+H)+

INTERMEDIATE 43

tert-butyl{(1R,3R)-7-chloro-1-[2-(difluoromethoxy)-6-ethenylphenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

Intermediate 42 (250 mg, 0.473 mmol), potassium vinyltrifluoroborate(92.3 mg, 0.662 mmol), cesium carbonate (308 mg, 0.944 mmol), and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (19.3 mg, 0.0236 mmol) were placed in a tube,and filled with argon. Degassed 1,4 dioxane (5 mL) and water (0.5 mL)were added and the resulting slurry was stirred at 110° C. overnight.The reaction mixture was cooled to ambient temperature, filtered andconcentrated in vacuo. The crude material was purified by preparativereverse phase HPLC (basic conditions) to afford 175 mg (78%) of thetitle compound. LCMS basic (ES+) RT 2.91 min., 476/478(M+H)+.

INTERMEDIATE 44

tert-butyl{(1R,3R)-7-chloro-1-[2-(difluoromethoxy)-6-formylphenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

Intermediate 43 (25 mg, 0.0526 mmol) was dissolved in 1,4 dioxane (0.4mL) and water (0.1 mL). At 0° C., sodium periodate (34 mg, 0.158 mmol)followed by osmium tetroxide (26 μl, 0.0021 mmol) were added . Thereaction mixture was allowed to warm to r.t. and stirred overnight. Thereaction was then diluted with EtOAc (2 mL) and water (2 mL). Theaqueous layer was extracted with EtOAc (2×2 mL). The combined organiclayers were washed with a saturated solution of sodium thiosulfate (2mL), brine, dried over magnesium sulphate, filtered and concentratedunder vacuum to afford the title compound which was used without furtherpurification. LCMS basic (ES+) RT 2.65 min., 478/480(M+H)+

INTERMEDIATE 45

(7R,14R)-11-chloro-1-(difluoromethoxy)-7,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

Intermediate 44 (0.0525 mmol) was dissolved in DCM/TFA (1/1). Thereaction mixture was stirred at r.t for one hour. The reaction mixturewas then concentrated under reduced pressure to afford the titlecompound as a TFA salt which was used without further purification. LCMSbasic (ES+) RT 2.29 min., 360/362 (M+H)+

INTERMEDIATE 46

Ethyl[(7R,14R)-11-chloro-1-(difluoromethoxy)-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]acetate

Example 12 (120 mg, 0.332 mmol) was dissolved in DMF (1 mL). Potassiumcarbonate (2 equiv., 0.663 mmol) and ethyl bromoacetate (1.2 equiv.,0.398 mmol) were added and the reaction mixture was stirred at r.t. for1 hour.

The mixture was filtered, rinsed with EtOAc and the volatiles removed invacuo. The residue was taken up with EtOAc, washed with water, driedover magnesium sulphate, filtered and concentrated in vacuo. The crudecompound was purified by reverse phase chromatography to afford 34 mg(23%) of the title compound. LCMS (ES+) 448/450 (M+H)⁺

INTERMEDIATE 47

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine-5(14H)-thione

Intermediate 23 (150 mg, 0.254 mmol) was solubilized in toluene (6 mL)before addition of Lawessons reagent (114 mg, 0.28 mmol). The slurry washeated overnight at 120° C. The reaction mixture was concentrated invacuo, and the residue taken up in DCM and filtered through a pad ofsilica gel eluting with DCM/MeOH (1/1) to afford 195 mg of the titlecompound as a brown solid used without further purification. LCMS acidic(ES+) RT 3.74 min. 608(M+H)⁺.

INTERMEDIATE 49(S)-N-[(1Z)-(2-Chloro-6-methoxyphenyl)methylidene]-2-methylpropane-2-sulfinamide

To a cooled (0° C.) solution of 2-chloro-6-methoxybenzaldehyde (15 g,87.93 mmol) in tetrahydrofuran (180 mL) was added sequentially(S)-2-methylpropane-2-sulfinamide (11.7 g, 96.7 mmol), tripotassiumphosphate (56 g, 264 mmol) and dipotassium hydrogen phosphate (46 g,263.8 mmol). The cooling bath was removed and the resultant suspensionwas stirred at r.t. for 18 hours. The reaction mixture was filteredthrough a pad of celite. The filtrate was diluted with EtOAc (250 mL),washed with brine (200 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to a crude residue. The crude material waspurified by flash column chromatography (0-50% EtOAc/heptanes) to afford22.7 g(94%) of the title compound as a pale yellow solid. LCMS Method 6(ES+) RT 1.61 min., 274.1 (M+H)⁺. ¹H NMR (500 MHz, Chloroform-d) δ 8.95(m, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.07 (dd, J=8.1, 0.8 Hz, 1H), 6.95-6.84(m, 1H), 3.88 (s, 3H), 1.29 (s, 9H).

INTERMEDIATE 50(S)—N—[(1R)-1-(2-chloro-6-methoxyphenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

To a suspension of zinc powder (27.9 g, 426.5 mmol) in anhydrous THF(100 mL) was added 1,2-dibromoethane (620 μL, 7.19 mmol) and the mixtureheated to 70° C. After 10 minutes at this temperature, the heating wasswitched off and the reaction stirred for a further 30 minutes (internaltemperature ca. 50° C.) and allowed to cool slowly to r.t. over 20minutes. Chloro(trimethyl)silane (910 μL, 7.17 mmol) was then addeddropwise. Effervescence and an exotherm to ˜40° C. was observed, alongwith coagulation of the zinc. The reaction was heated to 50° C. for 10min then allowed to cool to r.t. 3-Bromoprop-1-ene (18.5 mL, 213.8 mmol)was then added drop-wise at r.t. An exotherm to ˜50° C. was observedduring addition and the addition rate controlled to maintain theexotherm. After completion of addition, the resultant grey suspensionwas heated to 70° C. for 15 minutes, then cooled first to r.t. over 30min, then to −40° C. Anhydrous THF (350 ml) was added, then a pre-cooledsolution of Intermediate 49 (19.5 g, 71.1 mmol) in dry THF (100 mL) wasadded dropwise whilst maintaining an internal reaction temperature ofbetween −35 and −40° C., then the resultant mixture stirred at −40° C.for 1 hour. The reaction was allowed to warm to r.t., decanted andfiltered through a sinter funnel to remove excess zinc. The solids werewashed with THF (2×80 mL). The filtrate was poured into saturatedaqueous ammonium chloride solution (500 mL) and shaken well, thenextracted with EtOAc (2×500 mL). The combined organic layers were washedwith brine (500 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to afford ˜56 gcrude yellow oil. This material waspurified by reverse-phase flash column chromatography (elution 0-100%MeCN (+0.1% NH₄OH)/H₂O (+0.1% NH₄OH)). The clean fractions wereextracted with EtOAc (2×3 L). The combined organics were dried oversodium sulfate, filtered and concentrated to dryness under vacuum toyield 16.8 g (74%) of the title compound as colourless viscous oil. LCMSMethod 6 (ES+) RT 1.63 min., 316.1 (M+H)+. ¹H NMR (250 MHz,Chloroform-d) δ 7.14 (t, J=8.2 Hz, 1H), 6.97 (dd, J=8.1, 0.9 Hz, 1H),6.87-6.72 (m, 1H), 5.70 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.26-4.91 (m,2H), 4.53 (s, 1H), 3.86 (s, 3H), 2.81 (dtt, J=21.4, 13.8, 7.6 Hz, 2H),1.10 (s, 9H).

INTERMEDIATE 51 (1 R) -1-(2-chloro-6-methoxyphenyl)but-3-en-1-amine

Intermediate 50 (12.7 g, 40.21 mmol) was dissolved in diethyl ether (40mL) and ethanol (20 mL) then 4M hydrogen chloride in 1,4-dioxane (31 mL)was added and the reaction mixture was stirred for 45 minutes. Thereaction mixture was partitioned between water (150 mL) and diethylether (150 mL). The organic layer was re-extracted with 1M aq HClsolution (150 mL). The aqueous layers were combined, basified to pH 10by addition of 6M aq NaOH solution and extracted with EtOAc (2×200 mL).The combined organic layers were dried over Na₂SO₄ and concentrated todryness under vacuum to yield 9.19 g (97%) of the title compound as apale yellow viscous oil. LCMS Method 6 (ES+) RT 1.49 min., 212.3 (M+H)⁺.¹H NMR (500 MHz, Chloroform-d) δ 7.10 (t, J=8.2 Hz, 1H), 6.96 (dd,J=8.1, 0.9 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 5.77 (ddt, J=17.2, 10.2, 7.2Hz, 1H), 5.11-4.92 (m, 2H), 4.56 (t, J=7.6 Hz, 1H), 3.86 (s, 3H), 2.61(hept, J=7.3, 6.9 Hz, 2H).

INTERMEDIATE 52tert-butyl-[1-[5-(2,5-difluoro-4-nitro-phenyl)pyrimidin-2-yl]-1-methyl-ethoxy]-dimethyl-silane

The title compound can be prepared from Intermediate 11 and1-bromo-2,5-difluoro-4-nitro-benzene by a palladium catalyzed Suzukicoupling following an analogous method to that described forIntermediate 12.

INTERMEDIATE 535-(2-{2-[(tert-butyldimethylsilyl)oxy]propan-2-yl}pyrimidin-5-yl)-N-[(1R)-1-(2-chloro-6-methoxyphenyl)but-3-en-1-yl]-4-fluoro-2-nitroaniline

Intermediate 51 (2.51 g, 10.67 mmol) and Intermediate 52 7 (4.96 g, 10.9mmol) were dissolved in acetonitrile (40 mL) and K₂CO₃ (4.4 g, 31.84mmol) was added. The reaction mixture was stirred at 80° C. overnight.The reaction mixture was diluted with EtOAc (100 mL) and washed withwater (2×75 mL), then brine (75 mL), dried (Na₂SO₄) and concentrated todryness under vacuum to yield 7 g(98%) of the title compound as anorange gum. LCMS Method 6 (ES+) RT 2.64 min., 601.1 (M+H)⁺. ¹H NMR (500MHz, Chloroform-d) δ 8.94-8.74 (m, 3H), 7.99 (d, J=10.7 Hz, 1H), 7.18(t, J=8.2 Hz, 1H), 7.00 (d, J=7.9 Hz, 2H), 6.83 (d, J=8.2 Hz, 1H), 5.80(ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.48-5.25 (m, 1H), 5.16 (d, J=16.8 Hz,1H), 5.07 (d, J=10.0 Hz, 1H), 3.88 (s, 3H), 3.04-2.86 (m, 1H), 2.79 (dt,J=13.3, 6.5 Hz, 1H), 1.70 (d, J=4.4 Hz, 6H), 0.90 (s, 9H), −0.02 (s,6H).

INTERMEDIATE 54(3R)-3-{[5-(2-{2-[(tert-butyldimethylsily)oxy]propan-2-yl}pyrimidin-5-yl)-4-fluoro-2-nitrophenyl]amino}-3-(2-chloro-6-methoxyphenyl)propanal

Potassium dioxido(dioxo)osmium hydrate (2:1:2) (75 mg, 0.2 mmol) wasadded in one portion to a stirred solution of Intermediate 53 (6.85 g,10.25 mmol), sodium periodate (13.1 g, 61.25 mmol) and2,6-dimethylpyridine (2.4 mL, 20.67 mmol) in a 3:1 mixture of1,4-dioxane and water (240 mL). The mixture was stirred overnight thensodium thiosulfate (11.3 g, 71.47 mmol) was added and the resultingmixture was stirred for 30 minutes before diluting with DCM (200 mL) andwater (200 mL). The biphasic mixture was stirred for a further 15minutes then the two layers were separated and the aqueous layer wasre-extracted with DCM (2×100 mL). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated in vacuo to yield 8.5 gofthe title compound as an orange gum. LCMS Method 6 (ES+) RT 2.74 min.,603.1 (M+H)⁺. ¹H NMR (250 MHz, Chloroform-d) δ 9.81 (s, 1H), 8.87 (d,J=1.6 Hz, 2H), 8.24-8.07 (m, 1H), 7.99 (d, J=10.7 Hz, 1H), 7.19 (d,J=8.2 Hz, 1H), 7.02 (dd, J=8.1, 1.0 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H),6.03 (td, J=9.3, 5.0 Hz, 1H), 5.62-5.45 (m, 1H), 3.94 (s, 3H), 3.53(ddd, J=17.6, 8.9, 1.6 Hz, 1H), 3.01 (dd, J=17.8, 4.8 Hz, 1H), 1.71 (s,6H), 0.91 (s, 9H), −0.01 (s, 6H).

INTERMEDIATE 55(R)-N-[(1Z,3R)-3-{[5-(2-{2-[(tert-butyldimethylsily)oxy]propan-2-yl}pyrimidin-5-yl)-4-fluoro-2-nitrophenyl]amino}-3-(2-chloro-6-methoxyphenyl)propylidene]-2-methylpropane-2-sulfinamide

To a solution of Intermediate 54 (8.5 g, 10.29 mmol) and(R)-2-methylpropane-2-sulfinamide (1.25 g, 10.3 mmol) in DCM (50 mL) wasadded dropwise titanium(4+) tetrapropan-2-olate (6.1 mL, 20.6 mmol) andthe reaction mixture was stirred at 40° C. under nitrogen for 3 hoursand 20 minutes. The reaction was diluted with DCM (100 mL) then quenchedby the addition of brine (50 mL). The resultant sticky suspension wasfiltered through celite and the celite washed with further DCM (2×100mL) and water (100 mL). The filtrate was separated and the aqueous layerwas re-extracted with DCM (100 mL). The combined organics were dried(Na₂SO₄) and concentrated to dryness under vacuum to yield approximately8 gof a crude orange gum. The crude product was purified on slica gel(DCM/EtOAc 100/0 to 95/5) to yield 3.61 g(50%) of the title compound asan orange gum. LCMS Method 6 (ES+) RT 2.56 min., 706.1 (M+H)⁺. ¹H NMR(500 MHz, Chloroform-d) δ 8.96-8.79 (m, 3H), 8.10 (dd, J=5.7, 3.6 Hz,1H), 7.99 (d, J=10.6 Hz, 1H), 7.21 (t, J=8.2 Hz, 1H), 7.11 (s, 1H), 7.02(d, J=8.1 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 5.88 (td, J=9.3, 4.9 Hz, 1H),3.92 (s, 3H), 3.63-3.46 (m, 1H), 3.11 (d, J=16.3 Hz, 1H), 1.71 (d, J=3.8Hz, 6H), 1.13 (s, 9H), 0.91 (s, 9H), -0.02 (s, 6H).

INTERMEDIATE 56N-[(1R,3R)-3-{[5-(2-{2-[(tert-butyldimethylsilyl)oxy]propan-2-yl}pyrimidin-5-yl)-4-fluoro-2-nitrophenyl]amino}-3-(2-chloro-6-methoxyphenyl)-1-cyanopropyl]-2-methylpropane-2-sulfinamide

Intermediate 55 (2.8 g, 3.96 mmol) was dissolved in anhydrous THF (50mL) under nitrogen and scandium triflate (400 mg, 0.81 mmol) was added,followed by sodium cyanide (220 mg, 4.5 mmol). The reaction mixture wasstirred under a flow of nitrogen overnight. The reaction mixture wasdiluted with EtOAc (100 mL) and washed with a saturated solution ofNaHCO₃ (75 mL). The aqueous layer was re-extracted with EtOAc (75 mL)and the combined organics were washed with saturated brine (75 mL),dried over Na₂SO₄, filtered and concentrated to dryness under vacuum.The crude product was purified on silica gel (heptane/EtOAc 100/0 to60/40) to yield to 1.52 g(44%) of the title compound as an orange gum.LCMS Method 6 (ES+) RT 2.41 min., 733.1 (M+H)⁺. ¹H NMR (500 MHz,Chloroform-d) δ 8.94-8.62 (m, 3H), 8.02 (d, J=10.5 Hz, 1H), 7.26-7.14(m, 2H), 7.03 (d, J=8.0 Hz, 1H), 6.85 (d, J=7.9 Hz, 1H), 5.81-5.61 (m,1H), 4.49-4.26 (m, 1H), 3.92 (s, 3H), 3.86 (d, J=9.4 Hz, 1H), 2.93 (ddd,J=14.4, 9.7, 4.6 Hz, 1H), 2.48-2.23 (m, 1H), 1.71 (d, J=2.4 Hz, 6H),1.19 (s, 9H), 0.90 (s, 9H), -0.03 (s, 6H).

INTERMEDIATE 57

2-{5-[(1R,3R)-3-amino-1-(2-chloro-6-methoxyphenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl}propan-2-ol

Intermediate 56 (1.52 g, 2.07 mmol) was dissolved in ethanol (16 mL) andtin (II) chloride (2.4 g, 12.66 mmol) was added, followed by 12M HCl(1.4 mL) . The reaction mixture was stirred at 80° C. for 90 minutes.The reaction mixture was cooled to r.t. , concentrated in vacuo toapproximately 1 mL. The concentrated solution was dissolved in DCM (50mL), basified with 2M aqueous NaOH solution until pH=10 and finallytreated with 10% aqueous KF solution (25 mL). The mixture was filteredand the solids were washed with DCM (2×20 mL). The filtrate wasseparated and the aqueous layer was re-extracted with DCM (30 mL). Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated to dryness under vacuum to yield the title compound (134 mg14%) as an off-white solid.

The original solids can be washed with further EtOAc to yield a secondcrop of the title compound after removal of the volatiles in vacuo. Ifrequired additional purification can be performed by flashchromatography on silica gel (eluted with 0 to 100% EtOAc in heptane,followed by 0 to 20% MeOH in EtOAc). LCMS Method 6 (ES+) RT 3.76 min.,468.1 (M+H)⁺. ¹H NMR (500 MHz, Chloroform-d) Major atropisomer-δ 8.71(d, J=1.3 Hz, 2H), 7.56 (t, J=10.2 Hz, 1H), 7.33-7.27 (m, 1H), 7.16 (d,J=8.1 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.66 (d, J=6.6 Hz, 1H), 6.19 (t,J=7.7 Hz, 1H), 4.74 (s, 1H), 4.60 (s, 2H), 3.61-3.52 (m, 1H), 3.38 (s,3H), 2.67 (dt, J=14.4, 7.6 Hz, 1H), 1.62 (s, 6H).

INTERMEDIATE 58

2-{5-[(1R,3R)-3-amino-1-(2-chloro-6-fluorophenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl}propan-2-ol

Intermediate 58 was prepared following an analogous 8 steps procedure tothat described for Intermediate 41 through to Intermediate 57, startingfrom 2-chloro-6-fluoro-benzaldehyde. to afford 1.1 g of the titlecompound as a beige solid. LCMS basic Method 3 (ES+) RT 2.02 min.,456.2/458.1 (M+H)+.

INTERMEDIATE 59

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]methanesulfonamide

To a mixture of Intermediate 40 (2.5 g, 5.8 mmol),N,N-diisopropylethylamine (1.22 mL, 6.97 mmol) in DCM (58.3 mL),methanesulfonyl chloride (0.6 mL, 8 mmol) was added at 0° C. and themixture was stirred at r.t for 2 hours. Water (30 mL) was added to thereaction mixture and extracted with CH₂Cl₂ (2×30 mL). The organic phasewas washed with saturated brine (20 mL) and the combined organic phaseswas dried with sodium sulphate, filtered and concentrated in vacuo togive a solid. The crude was triturated in diethylether, filtered, washedtwice with diethylether then hexane and dried to give the title compound(2.8 g, 5.53 mmol, 95% yield) as a brown solid. LC/MS Method 3: RT 2.11mins (pH 10), m/z 506 and 508.

INTERMEDIATE 60

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2 ,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

Intermediate 38 (5 g, 11.64 mmol) and triphenylphosphine (3.7 g, 14mmol) were added to a round bottom flask followed by acetic acid (0.7mL, 10 mmol) and THF (12 mL). The reaction mixture was cooled down to 0°C. and DIAD (3.4 mL, 17 mmol) in THF (12 mL) was added dropwise. Themixture was stirred at 0° C. for 2 hours. The reaction mixture waswarmed to ambient temperature and the crude mixture was extracted withEtOAc (3×20 mL). The organic phase was washed with saturated NaHCO₃ (20mL) and saturated brine (20 mL), the combined organic phases was driedwith sodium sulphate, filtered and concentrated in vacuo to give an oilwhich was purified by flash chromatography in silica gel (0 to 80% EtOAcin Hexane) to afford[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]acetate.The material was dissolved in MeOH (6.3 mL) and stirred with potassiumcarbonate (1.6 g, 12 mmol) for 45 minutes, the solid was filtered andwashed with MeOH (30 mL) and water (10 mL) to give the title compound(4.3 g, 10 mmol, 86% yield) as a white solid. LC/MS Method 3: RT 2.07mins (pH 10), m/z 429 and 431.

INTERMEDIATE 612-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol

2-(5-bromo-4-methyl-pyrimidin-2-yl)propan-2-ol (1 g, 4.33 mmol),bis(pinacolato)diboron (2 equiv., 8.65 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.05 equiv., 0.22 mmol), potassium acetate (4equiv., 17.31 mmol) and 1,4-dioxane (5 mL) were placed in vial and thendegassed. The mixture was then heated at 105° C. for 2 hours.

The reaction mixture was cooled and partitioned between EtOAc and water.The organic layer was dried over Na₂SO₄ and evaporated to give a darkbrown solid, stored at 0° C. and used successfully in ensuing reactionsafter a period of several days.

Alternatively, intermediate 61 may be prepared by applying the followingprocedure: 2-(5-bromo-4-methylpyrimidin-2-yl)propan-2-ol (8 g, 34.6mmol), BISPIN (9.23 g, 36.3 mmol) and potassium acetate (10.2 g, 104mmol) were combined in 1,4-dioxane (300 mL). Argon was bubbled throughthe mixture over 10 minutes. Then PdCl₂(dppf) (0.76 g, 1.04 mmol) wasadded and the mixture was stirred at 100° C. The reaction mixture wascooled to room temperature and filtered over a plug of celite and rinsedwith EtOAc. The combined filtrate was concentrated under reducedpressure to give the title compound as dark brown oil (16.9 μ) which wasused as such.

¹H NMR (300 MHz, Chloroform-d) δ 8.90 (s, 1H), 5.04 (s, 1H), 2.71 (s,3H), 1.57 (s, 6H), 1.36 (s, 12H). LC/MS Method 9: 2.15 minutes, [M+H]⁺:278/279/280.

INTERMEDIATE 62 6-bromo-7-fluoroimidazo[1,2-c]pyridine-2-carboxylate

5-bromo-4-fluoropyridin-2-amine (100 g, 0.52 mol) was dissolved indioxane (200 mL) and added slowly to a solution of ethyl3-bromo-2-oxopropanoate (70 mL, 0.54 mol) in 1,4-dioxane (800 mL) andstirred at r.t. for 1.5 hours. Further 1,4-dioxane (400 mL) was addedand the mixture heated to 95° C. and stirred overnight. The mixture wascooled to r.t and concentrated in vacuo. The residue was dissolved inwater (700 mL) and basified to pH ˜9 with saturated aqueous sodiumbicarbonate solution. The resulting solid was filtered and washed withwater (2×200 mL) and diethyl ether (300 mL). The solid was dried invacuo at 40° C. overnight to give the title compound (133 g, 86%) as apeach coloured solid. Method 7 HPLC-MS: MH+m/z=288/290, RT=1.08 min(96%). ¹H NMR (500 MHz, Chloroform-d) δ 8.35 (d, J=6.3 Hz, 1H), 8.11 (s,1H), 7.39 (d, J=8.5 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz,3H).

INTERMEDIATE 63 {6-bromo-7-fluoroimidazo[1,2-a]pyridin-2-yl}methanol

Intermediate 62 (28.5 g, 95.3 mmol) was dissolved in anhydrous THF (500mL) and cooled to −10° C. under nitrogen. 1M diisobutylaluminum hydridein heptane (200 mL) was added dropwise over -30 minutes and the reactionmixture was stirred at −10° C. under nitrogen for 30 minutes thenallowed to warm to 10° C. under nitrogen over 1 hour. The reactionmixture was cooled to −50° C. and quenched by dropwise addition ofsaturated aqueous solution of Rochelle's salt (150 mL), stirred at −50°C. for 30 minutes, then allowed to warm to ambient temperature. Themixture was diluted with water (250 mL) and extracted with EtOAc (3×1L).The aqueous layer was filtered through celite and extracted with EtOAc(3×500 mL). The combined organics were dried (Na₂SO₄) and concentratedunder vacuum to yield the title compound (22.5 g, 93%) as a yellowsolid. Method 8 HPLC-MS: MH+m/z=245/247, RT=2.93 min (94%). ¹H NMR (500MHz, DMSO-d₆) δ 9.03 (d, J=6.7 Hz, 1H), 7.74 (s, 1H), 7.54 (d, J=9.8 Hz,1H), 5.23 (t, J=5.2 Hz, 1H), 4.56 (d, J=4.4 Hz, 2H).

INTERMEDIATE 643-[6-bromo-7-fluoro-2-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl]-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoicacid

Intermediate 63 (22.4 g, 84.02 mmol),2-chloro-6-(difluoromethoxy)benzaldehyde (20.1 g, 92.4 mmol),2,2-dimethyl-1,3-dioxane-4,6-dione (13.3 g, 92.4 mmol), L-proline (532mg, 4.62 mmol) and MgSO₄ (15.2 g, 126 mmol) were suspended in anhydrousacetonitrile (110 mL), warmed to 100° C. and stirred under N₂(g)overnight. The mixture was cooled to RT, diluted with acetonitrile (100mL) and filtered over a sintered glass funnel. The filter cake wasfurther washed with acetonitrile (50 mL) and the combined filtratetreated with 6M sodium hydroxide in water (42 ml) and stirred at ambienttemperature for 1 hour. The mixture was acidified (to pH 4) by treatmentwith 6M HCl (aq) then concentrated under vacuum to give a tan solid. Thesolid thus obtained was slurried in water (100 mL) for 2 hours thenfiltered to give the title compound (41.8 g, 83%) as a beige powder.Method 7 HPLC-MS: MH+m/z 493/495, (M-H)⁻m/z 491/493 RT 0.91 min (84%),¹H NMR (500 MHz, DMSO-d₆) δ 8.44 (d, J=6.5 Hz, 1H), 7.65 (d, J=9.3 Hz,1H), 7.41-7.37 (m, 2H), 7.19 (t, J=75.0 Hz, 1H), 7.17 (d, J=4.9 Hz, 1H),5.37 (dd, J=8.7, 6.8 Hz, 1H), 4.64-4.51 (m, 2H), 3.47 (dd, J=16.5, 6.7Hz, 1H), 3.29 (dd, J=16.5, 8.8 Hz, 1H).

INTERMEDIATE 656-bromo-3-{2-carboxy-1-[2-chloro-6-(difluoromethoxy)phenyl]ethyl}-7-fluoroimidazo[1,2-a]pyridine-2-carboxylicacid

Chromium trioxide (167 mg, 1.66 mmol) and periodic acid (81.0 g, 355mmol) were suspended in MeCN:H₂O (800 mL: 8 mL). The resulting mixturewas added to a stirred suspension of Intermediate 64 (41.8 g, 71.0 mmol)in MeCN:H₂O (312 mL: 2.4 mL). The resulting mixture was stirred at r.tovernight then filtered through a sintered glass funnel. The resultingpale green filter cake was washed with acetonitrile (4×50 mL) and thefiltrate concentrated under vacuum to give a gummy orange solid. Thiswas partitioned between EtOAc (500 mL) and water (250 mL). The layerswere separated and the aqueous phase further extracted with EtOAc (2×150mL). The combined organic phase was washed with water (3×250 mL), dried(MgSO₄), filtered and concentrated under vacuum to leave an orangepaste. This was slurried with water (200 mL) for 72 hours (weekendperiod) and filtered. The resulting yellow solid was washed with water(100 mL) and dried in vacuo at 40° C. to give the title compound (39.1g, 96%) as a pale yellow powder. Method 7 HPLC-MS: MH+m/z 507/509, RT1.00 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 12.39 (s, 2H), 8.73 (d, J=6.6Hz, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.39-7.30 (m, 2H), 7.16-7.11 (m, 1H),7.10 (t, J=75.0 Hz, 1H), 5.79 (t, J=8.4 Hz, 1H), 3.46 (dd, J=17.3, 9.2Hz, 1H), 3.20 (dd, J=17.3, 7.7 Hz, 1H).

INTERMEDIATE 66 Ethyl 6-bro mo-3-{1-[2-chloro-6-(difluoromethoxy)phenyl]-3-ethoxy-3-oxopropyl}-7-fluoroimidazo[1,2-a]pyridine-2-carboxylate

Potassium carbonate (25.0 g, 180 mmol) and iodoethane (14.6 ml, 181mmol) were added to a stirred solution of Intermediate 65 (34 g, 60.3mmol) in anhydrous DMF (350 mL) at r.t. The mixture was stirred under anatmosphere of nitrogen overnight then added slowly to vigorously stirredmixture of ice/water (1.2 L). After stirring at RT for a further 4hours, the resulting light beige solid was filtered under vacuum and thefilter cake slurried with water (50 mL). The solid was dried in vacuo at40° C. to give the title compound (31.5 g, 88%) as a light beige powder.Method 7 HPLC-MS: MH+m/z 564 RT 1.29 mins.

¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (d, J=6.5 Hz, 1H), 7.77 (d, J=9.2 Hz,1H), 7.40-7.33 (m, 2H), 7.30-6.96 (m, 2H), 5.82 (t, J=8.5 Hz, 1H), 4.23(qq, J=7.0, 3.8 Hz, 2H), 3.98 (q, J=7.0 Hz, 2H), 3.49 (dd, J=17.1, 8.9Hz, 1H), 3.27 (dd, J=14.8, 7.7 Hz, 1H), 1.24 (t, J=7.1 Hz, 3H), 1.03 (t,J=7.1 Hz, 3H).

INTERMEDIATE 67

Ethyl11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-5-oxo-1,7-diazatricyclo[6.4.0.0²,⁶]dodeca-2(6),7,9,11-tetraene-4-carboxylate

Intermediate 67 was prepared from Intermediate 66 according to themethod described for Intermediate 33. The crude material was purified byflash column chromatography (SiO₂, 800 μ) eluting with a stepwisegradient in 500 mL vessels of 15-50% EtOAc in heptanes then 100% EtOActo afford the title compound as a yellow/orange solid. (13.3 g, 50%).Method 7 HPLC-MS: MH+m/z 517/519, RT 1.21 min (99%), ¹H NMR (500 MHz,DMSO-d₆) δ 8.51-8.34 (m, 1H), 7.94-7.83 (m, 1H), 7.56-7.42 (m, 2H),7.39-6.68 (m, 2H), 5.77-5.63 (m, 1H), 4.28-4.13 (m, 2H), 4.07-4.00 (m,1H), 1.27-1.19 (m, 3H).

INTERMEDIATE 68

11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0.0²,⁶]dodeca-2(6),7,9,11-tetraen-5-one

Intermediate 68 was prepared from Intermediate 67 (13.3 g, 25.7 mmol)according to the method described for Intermediate 34 to give the titlecompound (11.3 g, 89%) as an orange foam. Method 7 HPLC-MS: MH+m/z444/446, RT 1.19 minutes.

¹H NMR (500 MHz, Chloroform-d) δ 7.79-7.58 (m, 1H), 7.47-7.27 (m, 3H),7.25-7.06 (m, 1H), 6.89-5.81 (m, 1H), 5.48-5.40 (m, 1H), 3.65-3.48 (m,1H), 3.30-3.09 (m, 1H).

INTERMEDIATE 69

(3R)-11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0.0²,⁶]dodeca-2(6),7,9,11-tetraen-5-one

The title compound was prepared by chiral separation of Intermediate 68into the constituent enantiomers and the isolation of the second elutingpeak according to the conditions outlined below:

Analytical Method: Liquid Chromatography

-   -   Column: Chiralcel OD 250×4.6 mm 5 μm    -   Temperature: 30° C.    -   Eluent: 100% MeOH +0.1% DEA    -   Flow rate: 1 ml/min    -   Enantiomer A: 4.943 min    -   Enantiomer B (Intermediate 69): 11.887 min

Preperative method, by SFC:

-   -   Column: Chiralcel OD 266×50 mm    -   Eluent: CO2+20% MeOH    -   Flow rate: 360 ml/min    -   Enantiomer A: depending on the amount injected (˜5.2 min)    -   Enantiomer B (Intermediate 69): depending on the amount injected        (˜8.5 min)

Optical rotation of Enantiomer B Intermediate 69: al, +117.6 (MeOH, conc0.255 g/100 mL, T =25° C., wavelength 589 nM, cell path 10 cm).

INTERMEDIATE 70

(R)—N-[(3R,5E)-11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0.0²,⁶]dodeca-2(6),7,9,11-tetraen-5-ylidene]-2-methylpropane-2-sulfinamide

Ti(OEt)₄ (1.59 mL, 2.48 mmol) was added a stirred solution ofIntermediate 69 (0.57 g, 1.22 mmol) in anhydrous THF (12 mL) at r.t.then (R)-2-methylpropane-2-sulfinamide (0.29 g, 2.43 mmol) was added andmixture was heated at 65° C. for 17 hours. The mixture was cooled tor.t., diluted with brine (10 mL), EtOAc (50 mL) and water (5 mL) andstirred for 15min. The resulting solids were removed by filtration andthe aqueous layer was further extracted with EtOAc (3×25 mL). Thecombined organic layers were washed with brine (25 mL), dried oversodium sulfate, filtered and concentrated in vacuo to afford the crudeproduct as a beige solid. Purification by column chromatography (SiO₂Biotage isolera), eluting with 0-100% EtOAc in heptanes afforded thetitle compound (600 mg, 90%) as a beige solid. Method 7 HPLC-MS: MH+m/z548, RT 1.20 min (99%),

¹H NMR (500 MHz, Chloroform-d) δ 7.76-7.58 (m, 1H), 7.43-7.39 (m, 1H),7.39-7.27 (m, 2H), 7.25-7.02 (m, 1H), 6.84-5.82 (m, 1H), 5.47-5.30 (m,1H), 4.52-4.33 (m, 1H), 3.61-3.47 (m, 1H), 1.36 (s, 9H).

INTERMEDIATE 71

(3R,5R)-11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0.0²,⁶]dodeca-2(6),7,9,11-tetraen-5-aminedihydrochloride

Sodium borohydride (90 mg, 2.38 mmol) was added in one portion to astirred solution of Intermediate 70 (600 mg, 1.09 mmol) in THF:water(14.7 mL:0.3 mL) under an atmosphere of nitrogen at −50° C. and thereaction maintained at this temperature for 30 minutes. The mixture wasslowly warmed to 0° C. over 2 hours then stirred for a further 1 hour.The mixture was quenched with MeOH (1 mL) and diluted with water (25mL). The intermediate was extracted with EtOAc (2×25 mL) and thecombined organic phases dried (MgSO₄), filtered and concentrated invacuo to leave an off-white foam (570 mg). This was dissolved in dioxane(10 mL) and treated with 4M HCl in dioxane (1.4 mL, 5.6 mmol). Themixture was stirred at RT for 30 minutes then concentrated to dryness toafford the title compound (480 mg, 67%) as an off-white solid. The titlecompound was used directly in the subsequent step without furtherpurification. Method 9 HPLC-MS: MH+m/z 446/448, RT 1.42 minutes.

INTERMEDIATE 72

2-{5-[(3R,5R)-5-amino-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0 .0²,⁶]dodeca-2(6),7,9,11-tetraen-11-yl]pyrimidin-2-yl}propan-2-ol

An aqueous solution of 2M K₂CO₃ (1.8 mL) was added to a stirredsuspension of Intermediate 71 (480 mg, 0.73 mmol) and2-[5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(232 mg, 0.88 mmol) in 1,4-dioxane (10 mL). The mixture was degassedunder a flow of nitrogen for 10 minutes then treated withbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; DCM;dichloropalladium (60 mg, 0.07 mmol) and heated to 105° C. for 1.5hours. The mixture was cooled to RT, diluted with EtOAc (30 mL) andfiltered through a pad of Celite. The filter cake was further washedwith EtOAc (2×20 mL). The filtrate was washed with water (25 mL) and theaqueous phase further extracted with EtOAc (2×25 mL). The combinedorganic phase was washed with brine (30 mL), dried (MgSO₄), filtered andconcentrated in vacuo to give the crude product (750 mg) as a dark brownoil. Purification by column chromatography (KP-NH, SiO₂, Biotageisolera) eluting with 50-100% EtOAc in heptane followed by 0-50% MeOH inEtOAc to give the title compound (260 mg , 71%) as an off white solid.The material was azeotroped twice with toluene prior to use in thesubsequent step. Method 8 HPLC-MS: MH+m/z 504, RT 3.86 minutes, ¹H NMR(500 MHz, DMSO-d₆) δ 8.90-8.78 (m, 2H), 8.18-7.90 (m, 1H), 7.68-7.54 (m,1H), 7.45-7.36 (m, 1H), 7.37-6.66 (m, 3H), 5.14-4.92 (m, 2H), 4.48-4.32(m, 1H), 3.57-3.34 (m, 1H), 2.95-2.54(m, 2H), 2.23-1.93 (m, 1H),1.51-1.47 (m, 6H).

INTERMEDIATE 73 2,2-Dichloro-3-oxocyclobutyl 2,2-dimethylpropanoate

To a stirred mixture of vinyl pivalate (30 g, 234 mmol) and zinc (31 g,474 mmol) in ether (250 mL) was added a solution of2,2,2-trichloroacetyl chloride (34 mL, 304 mmol) in ether (250 mL)dropwise over 2.5 hours in a water bath while maintaining the reactiontemperature between 15-30° C. Reaction was filtered through Celite andwashed through with EtOAc (200 mL). The filtrate was washed with water(200 mL), brine (200 mL), dried over sodium sulfate and concentratedunder vacuum to afford the title compound (68 g, 97% at 80% purity) asan orange liquid.

δH (500 MHz, CDCl₃) ppm 5.40 (dd, J=8.4, 6.2 Hz, 1H), 3.70 (dd, J=18.9,8.4 Hz, 1H), 3.39 (dd, J=18.9, 6.2 Hz, 1H), 1.28 (s, 9H).

INTERMEDIATE 74 3-Oxocyclobutyl 2,2-dimethylpropanoate

Zinc (74 g, 1.1 mol) was added to acetic acid (200 mL) with stirring andthe suspension was cooled in an ice bath. Intermediate 73 (80%, 68 g,228 mmol) in acetic acid (300 mL) was added dropwise over 2 hours. Uponcompletion of addition, the reaction was warmed to r.t and stirred for1.5 hours. The reaction was filtered washed with DCM (100 mL). Thefiltrate was diluted with EtOAc (800 mL) and washed sequentially withwater (3×250 mL), saturated aqueous NaHCO₃ solution (3×250 mL) and brine(50 mL). The organic phase was dried over sodium sulfate andconcentrated under vacuum to give crude product as a brown oil (30 μ)which was purified by dry flash chromatography on silica gel elutingwith 0-10% EtOAc in heptanes to afford the title compound (11 g, 28%) asa clear colourless oil

δH (500 MHz, CDCl₃) 5.26-5.19 (m, 1H), 3.51-3.40 (m, 2H), 3.19-3.07 (m,2H), 1.22 (s, 9H).

INTERMEDIATE 75 3-(5-Bromopyrimidin-2-yl)-3-hydroxycyclobutyl2,2-dimethylpropanoate

5-bromo-2-iodopyrimidine (16.7 g, 58.8 mmol) was dissolved in DCM (200mL) with stirring and cooled to −78° C. under N₂. 2.5 M n-BuLi in hexanein hexane (23.5 mL) was added dropwise and stirred for 20 minutes at−78° C. Intermediate 74 (10 g, 58.8 mmol) in DCM (50 mL) was cooled in adry ice bath and added in one portion. The reaction was stirred at −78°C. for 10 minutes. The reaction was quenched by addition of saturatedaqueous NH₄Cl solution (20 mL) and allowed to warm to r.t., saturatedaqueous NH₄Cl solution (50 mL) was added and the mixture was extractedwith DCM (2×100 mL). The combined organic extracts were dried oversodium sulfate and concentrated under vacuum. The crude product waspurified by column chromatography using 0-30% EtOAc in heptane to affordthe title compound (7.6 g, 35%) as a yellow solid.

δH (500 MHz, CDCl₃) 8.78 (s, 2H), 5.22-5.14 (m, 1H), 3.03-2.93 (m, 2H),2.67-2.58 (m, 2H), 1.22 (s, 9H).

INTERMEDIATE 76 1-(5-Bromopyrimidin-2-yl)cyclobutane-1,3-diol

Intermediate 75 (90%, 6 g, 16.4 mmol) was dissolved in MeOH (120 mL) andK₂CO₃ (11.3 g, 82 mmol) was added and the reaction stirred for 18 hoursat r.t. The reaction was diluted with DCM (400 mL) and washed with water(150 mL). The aqueous phase was extracted with DCM (200 mL). Thecombined organic extracts were dried over sodium sulfate andconcentrated under vacuum to afford the title compound (2.94 g, 73%) asan off-white solid.

δH (500 MHz, DMSO-d₆) 8.98 (s, 2H), 5.63 (s, 1H), 5.08 (d, J=6.2 Hz,1H), 4.09-3.92 (m, 1H), 2.87-2.79 (m, 2H), 2.28-2.14 (m, 2H).

INTERMEDIATE 77 3-(5-Bromopyrimidin-2-yl)-3-hydroxycyclobutan-1-one

To a stirred solution of Intermediate 76 (2 g, 8.1 mmol) in DCM (200 mL)was added Dess-Martin periodinane (4.1 g, 9.8 mmol). The reaction wasstirred for 18 hours and the resulting suspension diluted with DCM (100mL) and washed with saturated aqueous NaHCO₃ solution (100 mL). Theaqueous layer was re-extracted with DCM (100 mL) and the combinedorganic extracts dried over sodium sulfate and concentrated. The crudeproduct was purified by chromatography on silica gel eluting with 0-30%EtOAc in heptanes to afford the title compound (1.37 g, 69%) as an offwhite solid.

δH (500 MHz, DMSO-d₆) 9.04 (s, 2H), 6.41 (s, 1H), 3.69-3.55 (m, 2H),3.37-3.21 (m, 2H).

INTERMEDIATE 783-(5-Bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilypoxy]cyclobutan-1-one

Intermediate 77 (1.37 g, 5.64 mmol) was dissolved in dry DMF (20 mL)with stirring under N₂ and cooled to 0° C. 1H-imidazole (1.9 g, 28.18mmol) was added followed by tert-butyl(chloro)dimethylsilane (2.0 g,13.5 mmol) and reaction was stirred at r.t for 20 hours. The reactionwas diluted with DCM (150 mL) and washed with water (3×50 mL). Theaqueous phase was re-extracted with DCM (50 mL). The combined organicextracts were dried over sodium sulfate and concentrated. The crudeproduct was purified by chromatography on silica gel eluting with 0-20%EtOAc in heptanes to afford the title compound (1.6 g79%) as a paleorange oil.

δH (500 MHz, DMSO-d₆) 9.06 (s, 2H), 3.78-3.66 (m, 2H), 3.44-3.34 (m,2H), 0.88 (s, 9H), 0.00 (s, 6H).

INTERMEDIATE 793-(5-Bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-1-methylcyclobutan-1-ol

Intermediate 78 (1.35 g, 3.78 mmol) was dissolved in dry ether (40 mL)under N₂ with stirring and cooled to 0° C. using an ice bath. 3M MeMgBrin diethylether (2.52 mL) was added dropwise and reaction stirred for 30minutes at 0° C. The reaction was quenched with saturated aqueous NH₄Clsolution (20 mL) and then water (20 mL). The mixture was extracted withEtOAc (2×50 mL), dried over sodium sulfate and concentrated to give ayellow oil. This was purified by chromatography on silica gel elutingwith 0-100% DCM in heptane followed by 0-20% EtOAc in DCM to afford thetitle compound as a mixture of separate cis and trans isomers (totalyield, 1.19 g, 84%) as clear oils.

Major isomer-cis

δH (500 MHz, CDCl₃) 8.79 (s, 2H), 3.10-3.03 (m, 2H), 2.59-2.51 (m, 2H),1.18 (s, 3H), 0.87 (s, 9H), −0.14 (s, 6H).

Minor isomer-trans

δH (500 MHz, CDCl₃) 8.79 (s, 2H), 2.78-2.63 (m, 4H), 1.49 (s, 3H), 0.95(s, 9H), 0.04 (s, 6H).

INTERMEDIATE 80 1-Chloro-2,5-difluoro-4-nitrobenzene

A suspension of 2-chloro-1,4-difluorobenzene (98 g, 660 mmol) inconcentrated sulphuric acid (250 ml, 4.69 mol) was cooled with anice/salt mixture after which a solution of nitric acid (29.1 ml, 693mmol) in sulphuric acid (100 ml, 1.88 mol) was added drop-wise over 1.5hours whilst maintaining the temperature between −5 and +2° C. After 30minutes, the reaction mixture was allowed to warm to ˜17° C. and slowlypoured onto ice with stirring. The formed solid was isolated byfiltration and the residue washed several times with water and air driedyielding the title compound (112 g, 88%) as a pale yellow powder.

¹H NMR (300 MHz, Chloroform-d) δ 7.94 (dd, J=7.9, 6.5 Hz, 1H), 7.45 (dd,J=9.8, 5.9 Hz, 1H).

INTERMEDIATE 812-(5-(2,5-difluoro-4-nitrophenyl)pyrimidin-2-yl)propan-2-ol

A mixture of Intermediate 80 (50 g, 258 mmol),2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propan-2-ol(69.6 g, 264 mmol) and sodium carbonate (54.8 g, 517 mmol) in1,4-dioxane (700 mL) and water (100 mL) was flushed with argon 3 times.Subsequently, tris(dibenzylideneacetone)dipalladium (5.91 g, 6.46 mmol)and tri-tert-butylphosphine tetrafluoroborate (7.50 g, 25.8 mmol) wereadded and the mixture was stirred at 80° C. overnight. The reactionmixture was cooled to r.t., filtered over celite and washed with EtOAc(1 L). The filtrate was washed with water (100 mL) and brine (2×200 mL)and the combined aqueous layers back-extracted with EtOAc (200 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatography(silica; 30% EtOAc in heptane). The product containing fractions werecombined, concentrated in vacuo and crystallised from iPrOH to give thetitle compound as an orange solid (55μ) which can be further purified ifrequired by trituration with di-isopropyl ether.

LCMS Method 11 RT=1.806 (99.5%); [M+H]⁺=296.

¹H NMR (300 MHz, Chloroform-d) δ 8.95 (d, J=1.5 Hz, 2H), 8.02 (dd,J=9.2, 6.1 Hz, 1H), 7.46 (dd, J=10.4, 6.0 Hz, 1H), 4.47 (s, 1H), 1.66(s, 6H).

INTERMEDIATE 82(S)-N-(2-bromo-6-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide.

(S)-2-methylpropane-2-sulfinamide (30 g, 248 mmol), potassium phosphate,dibasic (129 g, 743 mmol) and phosphoric acid, potassium salt (158 g,743 mmol) were added to a cooled solution of2-bromo-6-(difluoromethoxy)benzaldehyde (68.3 g, 272 mmol) in anhydrousTHF (500 mL) at 0° C. The reaction mixture was allowed to warm to r.t.and stirred overnight. The bulk of the THF was removed in vacuo andwater and Et₂O were added to the residue. The layers were separated andthe aqueous phase extracted with Et₂O. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated in vacuoyielding the title compound (90 μ) as a dark oil which was used as suchin the next reaction. LCMS Method 11: RT=2.084 (97.6%); [M+H]⁺=354/356(Br pattern).

¹H NMR (300 MHz, Chloroform-d) δ 8.84 (s, 1H), 7.58 (dd, J=7.9, 1.2 Hz,1H), 7.33 (t, J=8.1 Hz, 1H), 7.28-7.20 (m, 1H), 6.57 (t, J=73.8 Hz, 1H),1.30 (s, 9H).

INTERMEDIATE 83(S)—N—((R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

Under a nitrogen atmosphere, 1,2-dibromoethane (2.19 ml, 25.4 mmol) wasadded to a suspension of zinc (100 g, 1.52 mol) in anhydrous THF (250mL). The suspension was warmed to mild reflux, allowed to cool down andheated to reflux again. This cycle was repeated twice more after whichTMSC1 (3.24 mL, 25.4 mmol) was added causing an exothermic reaction.After 15 minutes, 3-bromoprop-1-ene (55.2 mL, 635 mmol) was addeddropwise at such a rate that the very light reflux was maintainedwithout external heating. The suspension was stirred for an additional30 minutes while allowing to cool to r.t. Stirring was stopped andexcess zinc allowed to separate. The grey supernatant solution wastransferred to a dropping funnel and the flask rinsed twice withanhydrous THF. This solution was added relatively fast to a solution ofcrude Intermediate 82 (89.9 g, 254 mmol) in anhydrous THF (1000 ml)which was pre-cooled to −60° C. (dry ice/acetone). After the additionwas complete, the cooling bath was removed and the reaction mixtureallowed to slowly warm to r.t overnight. The reaction mixture wasquenched by adding saturated aqueous NH₄Cl solution (20 mL) and someice. The bulk of the THF was removed in vacuo and saturated aqueousNH₄Cl solution was added to the residue until almost no solids remained.This mixture was extracted with Et₂O (3×200 mL). The combined organiclayers were washed with saturated aqueous NH₄Cl solution, water andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo yieldingthe title compound (98.9 μ) as a yellow-orange oil which was used assuch in the next reaction.

LCMS Method 10: RT=3.183 (84.1%); [M-41]⁻¹=396/398 (Br pattern); d.e.:94.5% (the other diastereomer elutes at 3.43 minutes).

¹H NMR (300 MHz, Chloroform-d) δ 7.43 (d, J=7.9 Hz, 1H), 7.14 (t, J=8.1Hz, 1H), 7.13-6.98 (m, 1H), 6.56 (t, J=73.8 Hz, 1H), 5.82-5.62 (m, 1H),5.19 (q, J=8.0 Hz, 1H), 5.10-4.95 (m, 2H), 4.40-4.03 (m, 1H), 3.00-2.65(m, 2H), 1.14 (s, 9H).

INTERMEDIATE 84(R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-amine

At 0° C., HCl (1 M in Et2O, 666 mL, 666 mmol) was added to a solution ofcrude Intermediate 83 (88.0 g, -222 mmol) in ethanol (240 mL). After 3hours, the reaction mixture was diluted with water and the layers wereseparated. The organic layer was extracted twice with aqueous HCl ((0.2M). The combined aqueous layers were made alkaline (pH=˜10) by slowlyadding saturated aqueous Na₂CO₃ solution and the aqueous mixture thusobtained was extracted 3 times with Et₂O. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo yielding the title compound (56.4 μ) as a dark orange oil whichwas used as such in the next reaction.

LCMS Method 11: RT=1.360 (93.7%); [M+H]⁺=292/294 (Br pattern).

¹H NMR (300 MHz, Chloroform-d) δ 7.41 (dd, J=7.6, 1.6 Hz, 1H), 7.14-6.98(m, 2H), 6.56 (t, J=73.5 Hz, 1H), 5.86-5.68 (m, 1H), 5.13-4.97 (m, 2H),4.59 (t, J=7.6 Hz, 1H), 2.61 (t, J=7.1 Hz, 2H), 1.85 (br s, 2H).

INTERMEDIATE 85(R)-2-(5-(5-((1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)amino)-2-fluoro-4-nitrophenyl)pyrimidin-2-yl)propan-2-ol.

Under a N₂ atmosphere, Intermediate 81 (54.2 g, 183 mmol), Intermediate84 (56.4 g, ˜183 mmol), and potassium carbonate (50.7 g, 367 mmol) weremixed in acetonitrile (anhydrous, 500 mL) and stirred at 80° C. for 2days. After cooling to r.t., the reaction mixture was filtered throughsand and rinsed with EtOAc. The filtrate was evaporated to give thetitle compound (106.1 μ) as a dark red oil that was used as such in thenext reaction.

¹H NMR (300 MHz, Chloroform-d) δ 8.83 (s, 2H), 8.70 (br d, J=7.0 Hz,1H), 8.03 (d, J=10.7 Hz, 1H), 7.49 (dd, J=7.0, 2.2 Hz, 1H), 7.24-7.10(m, 2H), 6.92 (br d, J=6.0 Hz, 1H), 6.58 (t, J=72.3 Hz, 1H), 5.91-5.73(m, 1H), 5.36 (q, J=8.1 Hz, 1H), 5.22 (dd, J=17.0, 1.4 Hz, 1H), 5.13 (d,J=10.1 Hz, 1H), 4.67-4.50 (m, 1H), 3.09-2.70 (m, 2H), 1.65 (s, 6H).

INTERMEDIATE 86(R)-N-(1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-5-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyrimidin-5-yl)-4-fluoro-2-nitroaniline.

Imidazole (60.1 g, 883 mmol) and tert-butyldimethylsilyl chloride (80 g,531 mmol) were added to a solution of crude Intermediate 85 (99.8 g,˜176 mmol) in anhydrous N,N-dimethylformamide (250 mL). The mixture waswarmed to 100° C. and stirred for 19 hours. After cooling to r.t., thereaction mixture was diluted with brine (1 L) and extracted with mixtureof heptane and EtOAc (1:1, 500 +200 mL). The combined organic layerswere washed with water (2×100 mL) and brine (100 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (silica; 5-15% EtOAc in heptane) to give the titlecompound (107.1 g, 72% (over 5 steps)) as a red oil.

LCMS Method 12: RT=3.01 (94.9%); [M+H]⁺=681/683 (Br pattern).

¹H NMR (300 MHz, Chloroform-d) δ 8.78 (s, 2H), 8.65 (br s, 1H), 8.00 (d,J=10.7 Hz, 1H), 7.44 (dd, J=6.8, 2.4 Hz, 1H), 7.19-7.08 (m, 2H),6.92-6.81 (m, 1H), 6.54 (t, J=72.4 Hz, 1H), 5.88-5.74 (m, 1H), 5.33 (q,J=8.0 Hz, 1H), 5.20 (dd, J=17.0, 1.4 Hz, 1H), 5.11 (d, J=10.1 Hz, 1H),3.01-2.71 (m, 2H), 1.69 (s, 3H), 1.68 (s, 3H), 0.89 (s, 9H), -0.05 (s,6H).

INTERMEDIATE 87(4R)-4-(2-bromo-6-(difluoromethoxy)phenyl)-4-((5-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyrimidin-5-yl)-4-fluoro-2-nitrophenyl)amino)butane-1,2-diol

Osmium tetroxide (4 wt % in water, 4.80 mL, 0.786 mmol) and4-methylmorpholine-4-oxide (50 wt % in water, 94 mL, 393 mmol) wereadded to a solution of Intermediate 86 (107.1 g, 157 mmol) in a mixtureof acetone (330 mL) and water (45 mL). The reaction mixture was stirredovernight at ambient temperature and concentrated in vacuo. The residuewas mixed with aqueous Na₂S₂O₃ solution (10 wt %, 200 mL) and extractedtwice with EtOAc. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo yielding the titlecompound (120.1 μ) as a dark red sticky oil that was used as such in thenext reaction.

LCMS Method 12: RT=2.58 (95.3%); [M+H]⁺=715/717 (Br pattern).

INTERMEDIATE 88(R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-(2-(2-((tert-butyldimethylsilypoxy)propan-2-yl)pyrimidin-5-yl)-4-fluoro-2-nitrophenyl)amino)propanal

A solution of crude Intermediate 87 (119 g, -155 mmol) in THF (250 mL)was diluted with water (200 mL). To the resulting suspension, sodiumperiodate (68 g, 318 mmol) was added and another portion of sodiumperiodate (10.3 g, 48.2 mmol) after 3 hours.

Stirring was continued for another hour after which the reaction mixturewas quenched with aqueous Na₂S₂O₃ (10 wt %, 300 mL). The solids werefiltered off and washed with EtOAc (500 mL). The organic layers wereseparated (some NaCl (s) added to enable layer separation) and theaqueous phase was extracted with EtOAc (200 mL). The combined organiclayers were washed with a mixture of water (100 mL) and brine (50 mL)and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated invacuo to give the title compound (106.6 μ) as a dark red thick syrupthat was used as such in the next reaction. LCMS Method 12: RT=2.73(72.9%); [M+H]⁺=683/685 (Br pattern) and RT=2.57 (19.5%); [M+H]⁺=701/703(Br pattern) product as hydrate. ¹H NMR (300 MHz, Chloroform-d) δ 9.81(s, 1H), 8.86 (d, J=1.5 Hz, 2H), 8.68 (br d, J=8.6 Hz, 1H), 7.99 (d,J=10.6 Hz, 1H), 7.45 (dd, J=6.8, 2.4 Hz, 1H), 7.22-7.09 (m, 3H), 6.66(t, J=72.2 Hz, 1H), 6.00 (td, J=9.0, 4.7 Hz, 1H), 3.55 (dd, J=17.9, 9.0Hz, 1H), 3.08 (br d, J=16.9 Hz, 1H), 1.71 (s, 3H), 1.70 (s, 3H), 0.89(s, 9H), -0.03 (s, 6H).

INTERMEDIATE 89(R)-N-((R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-(2-(2-((tert-butyldimethylsilypoxy)propan-2-yl)pyrimidin-5-yl)-4-fluoro-2-nitrophenyl)amino)propylidene)-2-methylpropane-2-sulfinamide

Titanium (IV) isopropoxide (87 g, 307 mmol, 91 mL) was added to asolution of crude Intermediate 88 (105 g, ˜154 mmol) and(R)-(+)-2-methyl-2-propanesulfinamide (18.63 g, 154 mmol) in DCM (180mL). After stirring overnight, the reaction mixture was poured out intoa mixture of water (300 mL) and kieselguhr (30 μ), stirred for 10minutes, and filtered. The yellow solid was washed several times withDCM. The layers of the filtrate were separated and the organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo yielding the titlecompound (114.5 μ) as a yellow-orange glass that was used as such in thenext reaction.

LCMS Method 12: RT=2.88 minutes; [M+H]⁺=786/788 (Br pattern).

INTERMEDIATE 90 (R)-N-((R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-(2-(2-((tertbutyldimethylsilyl)oxy)propan-2-yl)pyrimidin-5-yl)-4-fluoro-2-nitrophenyl) amino)propylidene)-2-methylpropane-2-sulfinamide

To a stirred solution of crude Intermediate 89 (103.6 g, -139 mmol) inDCM (500 mL) was added yttrium(III) trifluoromethanesulfonate (3.53 g,6.58 mmol). The flask was sealed with a suba seal and to the resultingmixture, trimethylsilyl cyanide (15.68 g, 158 mmol, 19.77 mL) was addedby syringe in a steady stream. After stirring for 5 days, the reactionmixture was concentrated in vacuo and co-evaporated with EtOAc yieldingthe title compound (101 μ) as a yellow-red foaming oil that was used assuch in the next reaction.

LCMS Method 13: RT=2.70 minutes; [M+H]⁺=813/815 (Br pattern).

INTERMEDIATE 91(R)-N-((3R)-3-((2-amino-5-(2-(2-((tertbutyldimethylsilyl)oxy)propan-2-yl)pyrimidin-5-yl)-4-fluorophenyl)amino)-3-(2-bromo-6-(difluoromethoxy)phenyl)-1-cyanopropyl)-2-methylpropane-2-sulfinamide

Under a N₂ atmosphere, platinum on charcoal (10 wt %, 13.88 g, 7.11mmol) was added to a mixture of crude Intermediate 90 (106 g, -147 mmol)and zinc(II) bromide (12.46 g, 55.3 mmol) in EtOAc (1000 mL).Subsequently, the reaction was purged with H₂ and stirred underatmospheric H₂ pressure for 3 days. The reaction mixture was flushedwith N₂, filtered over kieselguhr and rinsed with EtOAc. The filtrate(˜1.5 L) was washed with water (500 mL) and brine, dried over Na₂SO₄,filtered and concentrated in vacuo yielding the title compound (109 μ)as a brown-yellow foaming oil that was used as such in the nextreaction.

LCMS Method 11: RT=1.360 (76.5%); [M+H]⁺=783/785 (Br pattern).

INTERMEDIATE 92

2-(5-((1R,3R)-3-amino-1-(2-bromo-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1Hbenzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol.

To a stirred solution of crude Intermediate 91 (109 g, -147 mmol) inethanol (1000 mL) was added HCl (4 M in dioxane, 69.5 mL, 278 mmol). Theresulting mixture was stirred at reflux for 8 hours and allowed to coolto r.t overnight. The reaction mixture was concentrated in vacuo andco-evaporated with ethanol. The residue was triturated in Et₂O (1.5 L)and the formed precipitate was isolated by filtration, washed with Et₂O,and dried on the filter. This material was taken up in iPrOH (250 mL)and stirred at reflux for 15 minutes. The resulting suspension wasstirred under N₂ while allowing to cool to r.t. The resulting thickviscous suspension was diluted with iPrOH (250 mL) and filtered througha glass filter. The residue thus obtained was dissolved in water (1.5 L)and Et₂O (500 mL) while stirring. The layers were separated and theorganic layer was extracted with aqueous HCl (0.1 M, 200 mL). Thecombined aqueous layers were washed with Et₂O (500 mL), made alkaline(pH=10) with NaOH (s, 40 μ), and extracted with DCM (2×500 mL). Thecombined DCM layers were dried over Na₂SO₄, filtered and concentrated invacuo. The residue thus obtained was co-evaporated with iPr₂O and Et₂Oyielding the title compound (40.6 g, 48%) as a green foam.

LCMS Method 10: RT=2.37 minutes; [M+H]⁺=548/550 (Br pattern).

¹H NMR (300 MHz, Chloroform-d): 3:2mixture of rotamers δ 8.74-8.70 (m,2H), 7.61 (d, J=8.2 Hz, 0.6H), 7.57 (d, J=11.2 Hz, 1H), 7.45 (dd, J=6.6,2.6 Hz, 0.4H), 7.37-7.28 (m, 1.4H), 7.04 (d, J=8.3 Hz, 0.6H), 6.71 (t,J=72.4 Hz, 0.4H), 6.59 (dd, J=12.0, 6.6 Hz, 1H), 6.23-6.13 (m, 1H), 5.92(dd, J=74.5, 70.9 Hz, 0.6H), 4.72 (br s, 1H), 4.61 (br s, 1H), 3.70-3.41(m, 1H), 2.77 (dt, J=13.5, 8.6 Hz, 0.4H), 2.63 (dt, J=13.7, 7.6 Hz,0.6H), 2.03 (br s, 2H), 1.62 (s, 3.6H), 1.61 (s, 2.4H).

INTERMEDIATE 93

Ethyl2-[[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]amino]acetate

Ethyl bromoacetate (91.3 mg, 0.54 mmol) was added to a solution ofpotassium carbonate (252 mg, 1.82 mmol), and Intermediate 92 (250 mg,0.45 mmol) in DMF (1.5 mL). The reaction mixture was stirred at 70° C.for 2 hours. The reaction mixture was cooled to ambient temperature andthe crude mixture was quenched with water and extracted with EtOAc (2×5mL). The organic phase was washed with saturated brine (5 mL), thecombined organic phases were dried with sodium sulphate, filtered andconcentrated in vacuo to give an oil which was purified by flashchromatography in silica gel (0 to 100% EtOAc in hexanes) to afford thetitle compound (220 mg, 76% yield) as a brown solid. LC/MS Method 3: RT2.06 mins (pH 10), m/z 634/636.

INTERMEDIATE 94

tert-butyl3-[[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazo1-3-yl]carbamoyl]azetidine-1-carboxylate

Intermediate 92 (550 mg, 1.00 mmol) was added to a solution of1-tert-butoxycarbonylazetidine-3-carboxylic acid (222 mg, 1.10 mmol,),HATU (432 mg, 1.10 mmol) and N,N-di-isopropylethylamine (0.38 mL, 2.2mmol) in DMF (20 mL). The reaction mixture was stirred at ambienttemperature for 3 hours. Water was added and the reaction mixtureextracted with EtOAc and the organic phases removed in vacuo to yield acrude product.The crude material was purified by column chromatographyover silica gel using hexane/ethyl acetate (0 to 100%) as eluent,yielding 640 mg (87%) of the title compound as an amorphous solid. LCMSbasic Method 3: RT 2.25 min, [M+H-BOC]⁺=631.

INTERMEDIATE 95

tert-Butyl3-{[(6R,12R)-11-(difluoromethoxy)-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]carbonyl}azetidine-1-carboxylate

To Intermediate 94 was added cesium acetate anhydrous (420 mg, 2.18mmol), cuprous iodide (170 mg, 0.87 mmol) and dimethyl sulfoxide (0.9mL). The mixture was seal and purged 3 times with nitrogen. The reactionmixture was stirred for 18 hours at 100° C. Water and ethyl acetate wereadded to the reaction mixture and the two layers were separated. Theaqueous layer was extracted with ethyl acetate and the combined organicswere filtered through a phase separator and the solvent was evaporated.The crude material was purified by column chromatography over silica gelusing hexane/ethyl acetate (0 to 100%) as eluent, yielding 158 mg (28%)of the title compound as a brown solid. LCMS Method 3: RT 2.72 min,[M+H]⁺=651

INTERMEDIATE 96

tert-butyl3-{[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]carbamoyl}azetidine-1-carboxylate

Intermediate 40 (250 mg, 0.58 mmol) was added to a solution of1-tert-butoxycarbonylazetidine-3-carboxylic acid (130 mg, 0.65 mmol),HATU (252 mg, 0.643 mmol) and N,N-diisopropylethylamine (0.18 mL, 1.0mmol) in DMF (11 mL). The reaction mixture was stirred at roomtemperature for 3 hours. Water was added to the reaction and the mixtureextracted with EtOAc (x3), dried (sodium sulphate), filtered andconcentrated in vacuo. The crude material was purified by columnchromatography over silica gel using hexane/ethyl acetate (0 to 100%) aseluent, yielding 280 mg (78%) of the title compound as an amorphoussolid.

LCMS Method 3: RT 2.48 minutes, [M+H]⁺=611/613.

INTERMEDIATE 97

tert-butyl3-{[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]carbonyl}azetidine-1-carboxylate

To Intermediate 96 (165 mg, 0.27 mmol) was added cesium acetate (130 mg,0.67 mmol), cuprous iodide (52 mg, 0.27 mmol) and dimethyl sulfoxide(0.3 mL). The mixture was sealed in a pressure tube and purged 3 timeswith nitrogen. The reaction mixture was stirred at 100° C. overnight.Water and ethyl acetate were added to the reaction mixture and the twolayers were separated. The aqueous layer was extracted with furtherethyl acetate. The combined organic layer was filtered through a phaseseparator and the solvent was evaporated. The crude material waspurified by column chromatography on silica gel using hexane/ethylacetate (0 to 100%) as eluent, yielding 85 mg (59%) of the titlecompound as a brown solid. LCMS Method 3: RT 2.63 min., [M+H]⁺=531/533.

INTERMEDIATE 98

cis-3-{[tert-butyl(dimethyl)silyl]oxy}-3-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}-1-methylcyclobutanol

The title compound was prepared from3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl],and Example 23 according to a method involving the same procedural stepsas those described for Example 20, to give, following purification bycolumn chromatography over silica gel using hexane/ethyl acetate (0 to100%) as eluent the title compound as a white solid (83 mg, 37% yield).

LC/MS Method 3: RT 2.73 minutes, [M+H]⁺=684.

INTERMEDIATE 99

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]pyridine-3-sulfonamide

Pyridine-3-sulfonyl chloride (1.1 eq, 0.6 mmol) was added to a solutionof Intermediate 92 (300 mg, 0.55 mmol) and N,N-diisopropylethylamine(0.24 mL, 1.3 mmol) in dichloromethane (2.8 mL) at room temperature. Themixture was stirred for lhour before solvent was partially evaporated.The crude material was purified by column chromatography on silica gelusing hexane/ethyl acetate (0 to 100%) as eluent, yielding 276 mg (73%)of the title compound. LCMS Method 3: RT 1.91 min. (pH 10), [M+H]+=689.

INTERMEDIATE 1001-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-3-(trifluoromethyl)azetidin-3-ol

To a solution of the trifluoroacetate salt of(trifluoromethyl)-3-aziditin-3-ol (5.8 g, 22.75 mmo1) and2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (5 g,20.75 mmo1) in acetonitrile (80 mL) was added dropwise triethylamine(9.5 mL, 68.5 mmol) and the resultant mixture stirred overnight. LC/MSshowed completion of reaction, concentrated to an off-white solid,ice-water was added, triturated, filtered, washed with cold water anddried by suction to give the title compound (6.1 g, 50%) as cream solid.¹H NMR (400 MHz, DMSO-d₆): δ 8.53 (s, 2H), 7.46 (s, 1H), 4.32 (m, 2H),4.10 (d, J=10.3 Hz, 2H), 1.29 (s, 12H). LC/MS Method 3:: m/z 346, RT1.09 min (pH=10).

INTERMEDIATE 101

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]methanesulfonamide

To a solution of Intermediate 92 (202 mg, 0.37 mmol) and4-dimethylaminopyridine (6 mg, 0.05 mmol) in DCM (4 mL) at 0° C. wasadded N,N-diisopropylethylamine (76 μL, 0.43 mmol) followed bymethanesulfonyl chloride (30 μL, 0.38 mmol). The reaction mixture wasstirred at 0° C. for 10 minutes and then at room temperature for 45minutes, after which time the reaction mixture was concentrated invacuo. The residue was purified by column chromatography (SiO₂, 25-100%EtOAc in hexane) to give the title compound (193 mg, 83%) as a yellowsolid. LCMS Method 3: (ES+) 626/628 (M+H)⁺, RT 1.90 minutes. LCMS Method4: (ES+) 626/628 (M+H)⁺, RT 1.86 minutes.

INTERMEDIATE 102

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]cyclopropanesulfonamide

To a solution of Intermediate 92 (151 mg, 0.28 mmol) and4-dimethylaminopyridine (5 mg, 0.04 mmol) in DCM (3 mL) at 0° C. wasadded N,N-diisopropylethylamine (58 μL, 0.33 mmol) followed bycyclopropanesulfonyl chloride (172 μL, 1.65 mmol). The reaction mixturewas stirred at 0° C. for 10 minutes and then at room temperature for 18hours, after which time the reaction mixture was partitioned between DCM(30 mL) and water (20 mL), the layers separated and the aqueousextracted with DCM (3×20 mL). The combined organics were dried (phaseseparator), and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, 25-100% EtOAc in hexane) to give the titlecompound (110 mg, 61%) as a purple solid. LCMS (ES+) Method 3: 652/654(M+H)⁺, RT 2.20 minutes. LCMS (ES+) Method 4: 652/654 (M+H)⁺, RT 2.01minutes.

INTERMEDIATE 103

2-[5-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-3-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]propan-2-ol

To a solution of Intermediate 92 (251 mg, 0.46 mmol) and potassiumcarbonate (252 mg, 1.82 mmol) in DMF (2 mL) was added(2-bromoethoxy)-tert-butyldimethylsilane (99 μL, 0.46 mmol) and reactionmixture stirred at 70° C. for 18 hours. The reaction mixture waspartitioned between EtOAc (25 mL) and water (25 mL), layers separatedand aqueous extracted with EtOAc (2×25 mL), the combined organics dried(phase separator) and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, 0-100% EtOAc in hexane) to give the titlecompound (128 mg, 39%) as a brown oil. LCMS (ES+) Method 3: 706/708(M+H)⁺, RT 3.10 minutes.

INTERMEDIATE 104

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]benzenesulfonamide

To a solution of Intermediate 92 (202 mg, 0.37 mmol) and4-dimethylaminopyridine (5 mg, 0.04 mmol) in DCM (4 mL) at 0° C. wasadded N,N-diisopropylethylamine (77 μL, 0.44 mmol) followed bybenzenesulfonyl chloride (49 μL, 0.38 mmol). The reaction mixture wasstirred at 0° C. for 5 minutes and then at room temperature for 1.5hours. The reaction mixture was concentrated in vacuo and the residuepurified by column chromatography (SiO₂, 0-60% EtOAc in hexane) to givethe title compound (178 mg, 70%) as a yellow solid.

LCMS (ES+) Method 3: 688/690 (M+H)⁺, RT 2.20 minutes.

LCMS (ES+) Method 4: 688/690 (M+H)⁺, RT 2.01 minutes.

INTERMEDIATE 105

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]-6-methoxy-pyridine-3-sulfonamide

To a solution of Intermediate 92 (150 mg, 0.27 mmol) and4-dimethylaminopyridine (5 mg, 0.04 mmol) in DMF (3 mL) at 0° C. wasadded N,N-diisopropylethylamine (57 μL, 0.33 mmol) followed by6-methoxypyridine-3-sulfonyl chloride (62 mg, 0.29 mmol). The reactionmixture was stirred at 0° C. for 5 minutes and then at room temperature30 minutes. The reaction mixture was concentrated in vacuo. The residuewas purified by column chromatography (SiO₂, 0-100% EtOAc in hexane) togive the title compound (148 mg, 75%) as a dark beige solid. LCMS (ES+)Method 3: 719/721 (M+H)⁺, RT 2.30 minutes. LCMS (ES+) Method 4: 719/721(M+H)⁺, RT 2.42 minutes. 6.1-1 (300 MHz, DMSO-d₆) 8.77-8.97 (m, 1H),8.71-8.77 (m, 3H), 8.19-8.26 (m, 1H), 7.59-7.68 (m, 1 H), 7.39-7.50 (m,2H), 7.38 (t, 1H, J73.4 Hz), 7.07 (d, 1H, J8.7 Hz), 6.65-6.71 (m, 1 H),6.04-6.21 (m, 1H), 5.22-5.44 (m, 1H), 5.05-5.07 (m, 1H), 3.96 (s, 3H),3.05-3.24 (m, 1H), 2.59-2.79 (m, 1H), 1.47-1.52 (m, 6H).

INTERMEDIATE 106

Ethyl[(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-oxo-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]acetate

To a solution of Intermediate 23 (100 mg, 0.169 mmol) in THF (4 mL) wasadded potassium bis(trimethylsilyl)amide (0.2 mL, 0.2 mmol, 1M in THF)at −78° C. and stirred for 40 minutes before the addition of ethylbromoacetate (25.0 μL, 0.225 mmol). The reaction mixture was stirred at−78° C. for 30 mins before being quenched with water. The mixture wasextracted with DCM (2×20 mL), and the organics were combined, dried withNa₂SO₄, filtered and concentrated in vacuo. The crude product wascolumned on silica eluting with 0-5% MeOH/DCM to give the title compound(88 mg). LC/MS: Method 3: RT 3.53 minutes.

INTERMEDIATE 107

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-(2,2,2-trifluoroethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5 ]benzodiazocin-5(14H)-one

To a solution of Intermediate 23 (90.0 mg, 0.152 mmol) in DMF (3.5 mL)were added cesium carbonate (250 mg, 0.767 mmol) and2-iodo-1,1,1-trifluoroethane (0.06 mL, 0.60 mmol) at ambienttemperature. The reaction mixture was heated at 150° C. for 3 hours.

The reaction mixture was partitioned between EtOAc (2×10 mL) and water(20 mL), and the organics were combined, dried with Na₂SO₄, filtered andconcentrated in vacuo. The crude product was progressed to the next stepwithout further purification.

LC/MS: Method 3 MFI⁺674, retention time 2.03 minutes.

INTERMEDIATE 108

(7R,14R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one

To a solution of Intermediate 23 (100.0 mg, 0.169 mmol) in THF (4.0 mL)was added potassium bis(trimethylsilyl)amide (0.20 mL, 0.20 mmol, 1M inTHF) at −78° C. followed by the addition of(2-bromoethoxyl)-tert-butyldimethylsilane (50.0 μL, 0.231 mmol). Thereaction mixture was heated in a microwave at 70° C. for 24 hours beforebeing quenched with aqueous saturated NH₄Cl and extracted with EtOAc(2×10 mL). The organics were combined, dried with Na₂SO₄, filtered andconcentrated in vacuo. The crude product was progressed to the next stepwithout further purification. LC/MS Method 3: ESI MH⁺750, retention time4.23 minutes.

INTERMEDIATE 109

(7R,14R)-11-[2-(2-{[tert-butyl(dimethypsilyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-(2-hydroxyethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(141)-one

To a solution of Intermediate 108 (80.0 mg, 0.107 mmol) in THF (5.0 mL)was added a solution of tetrabutylammonium fluoride (0.20 mL, 0.20 mmol,1M in THF) at ambient temperature and the mixture was stirred for 72hours. The reaction mixture was partitioned between water (10 mL) andDCM (3×10 mL), and the organics were combined, dried with Na₂SO₄,filtered and concentrated in vacuo. The crude product was progressed tothe next step.

LC/MS Method 3: ESI MH⁺636, retention time 3.21 minutes.

INTERMEDIATE 110

(7R,14R)-11-chloro-1-(difluoromethoxy)-6-(trideutero)methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)one

To a solution of Example 11 (90.0 mg, 0.24 mmol) in THF (4 mL) was addeda solution of KHMDS in THF (1M, 0.25 mL, 0.25 mmol) dropwise at −78° C.and the mixture was stirred for 30 minutes before the addition of CD₃I(30.1 μL, 0.48 mmol). The reaction mixture was warmed to 0° C. andstirred for 3 hours. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution, extracted with EtOAc, dried with Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica eluting with 0-10% MeOH/EtOAc to givethe title compound (95 mg, 99%). LC/MS Method 3: ESI MH⁺393, retentiontime 1.93 minutes.

INTERMEDIATE 111

tert-butyl(2-{5-[(7R,14R)-1-(difluoromethoxy)-6-(trideutero)methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

To a solution of tert-butylN-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]ethyl]carbamate(260 mg, 0.72 mmol) and Intermediate 110 (94 mg, 0.24 mmol) in1,4-dioxane (3 mL) were added K₃PO₄ (294 mg, 1.40 mmol), tricyclohexylphosphonium tetrafluoroborate (15 mg, 0.04 mmol) andtris(dibenzylideneacetone) dipalladium(0) (28 mg, 0.03 mmol) were added.The mixture was degassed for 10 minutes with nitrogen before heating at110° C. for 18 hours. The reaction mixture was quenched with water andextracted with EtOAc (2×10 mL), dried with Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica eluting with 0-10% MeOH/DCM to give the titlecompound (40 mg, 28%). LC/MS Method 3: ESI MH⁺594, retention time 2.10minutes.

INTERMEDIATE 112

rac2-(5-{(1R,3R)-3-amino-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl}-4-methylpyrimidin-2-yl)propan-2-ol

Intermediate 61 (0.15 g, 0.6 mmol) and potassium acetate (0.15 g, 1.5mmol) were suspended in anhydrous 1,4-dioaxane (5 mL) in a sealablevessel. The mixture was stirred and degassed thoroughly under a streamof N₂(g) for 15 min then treated withbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron;dichloromethane; dichloropalladium (0.02 g, 0.02 mmol), and a solutionof Intermediate 71 (82%, 0.25 g, 0.4 mmol) in a mixture of dioxane (1mL) and 2M K₂CO₃ in water (1.24 ml) was added and the mixture warmed to100° C. overnight. After cooling to room temperature the mixture wasdiluted with EtOAc (25 mL) and filtered over a pad of celite. Thefiltrated was washed with water (10 mL), dried (MgSO₄), filtered andconcentrated in vacuo to give the crude product (0.4 g) as a brown gum.Column chromatography (C18, biotgae isolera, 60 μ) eluting with 0 to 50%acetonitrile in water spiked with 0.1% NH4OH afforded the title compound(0.15 g, 58%) as an orange glass. The material was azeotroped twice withtoluene prior to use in the subsequent step. Method 8 HPLC-MS: MH+m/z518, RT 1.43 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 8.56-8.51 (m, 1H),7.99-7.77 (m, 1H), 7.63-7.53 (m, 1H), 7.43-7.31 (m, 2H), 7.29-7.24 (m,1H), 7.06-6.73 (m, 1H), 5.10-4.90 (m, 2H), 4.47-4.31 (m, 1H), 3.52-3.40(m, 1H), 2.34-2.27 (m, 3H), 2.03-1.81 (m, 3H), 1.52-1.45 (m, 6H).

INTERMEDIATE 113

(7R,14R)-11-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-4-methylpyridin-3-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Example 11 (450 mg, 1.20 mmol) andtert-butyl-dimethyl-[1-methyl-1-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)-2-pyridyl]ethoxy]silane (483 mg, 1.86 mmol), by apalladium catalyzed Suzuki coupling according to a method involving thesame procedural steps as those described for Example 20. The crudeproduct was purified by flash chromatography (SiO₂, 0 to 100% EtOAc inDCM and then 1 to 10% MeOH in EtOAc) to obtain the title compound (650mg, 81%) as a brown solid. LCMS Method 3 (ES+) RT 3.20 min, 605 (M+H)⁺.

INTERMEDIATE 114 tert-butylN-[1-(5-bromopyrimidin-2-yl)-1-methyl-ethyl]carbamate

2-(5-bromopyrimidin-2-yl)propan-2-amine (200 mg, 0.92 mmol) wasdissolved in THF (5 mL) and di-tert-butyl dicarbonate solution (1.0M)(1.3 mL, 1.3 mmol) in THF added. After 2 hours the solvents were removedin vacuo to afford the title compound as an orange gum (300 mg, 92%).LCMS Method 3 (ES+) RT 1.88 min, 338.0/340.0 (M+Na)⁺.

INTERMEDIATE 115

tert-butyl (2-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

The title compound was prepared from Example 11 (300 mg, 0.80 mmol) andIntermediate 114 (252 mg, 0.80 mmol) in accordance with the Methoddescribed for Example 70. The crude product was purified by flashchromatography in (SiO₂, 0 to 100% EtOAc in DCM and then 1 to 10% MeOHin EtOAc) to obtain the title compound (154 mg, 33%).

LCMS Method 3 (ES+) RT 1.43 min, 577.2 (M+H)⁺

INTERMEDIATE 116

tert-butyl (2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

The title compound was prepared from Example 10 (50 mg, 0.13 mmol) andIntermediate 114 (100 mg, 0.32 mmol) in accordance with the Methoddescribed for Example 70. The product was purified by flashchromatography (SiO₂, 0 to 100% EtOAc in DCM and then 1 to 10% MeOH inEtOAc) to obtain the title compound (55 mg, 71%). LCMS Method 3 (ES+) RT2.16 min, 595.2 (M+H)⁺

INTERMEDIATE 117

tert-butyl{(1R,3R)-1-[2-acetyl-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

To a degassed solution of Intermediate 42 (1.4 g, 2.6 mmol) in drytoluene (30 mL) under argon were added tributyl(1-ethoxyvinyl)tin (1.1mL g, 3.2 mmol) and bis(triphenylphosphine)-palladium(II)dichloride (100mg, 0.141 mmol). The reaction mixture was heated at 105° C. for 48hours. Further Tributyl(1-ethoxyvinyl)tin (0.7 g, 2.0 mmol) andbis(triphenylphosphine)palladium(II)-dichloride (64 mg, 0.0912 mmol)were added and the reaction mixture was heated for an additional 5 hoursat 105° C. The reaction mixture was cooled to room temperature andpoured onto a saturated aqueous solution of KF. The mixture wasextracted with ethyl acetate, filtered over celite, dried over MgSO₄,filtered and concentrated in vacuo. The crude compound was re-dissolvedin THF (50 mL), p-toluene sulfonic acid (200 mg) and water (5 mL) wasadded and the mixture was heated at 45° C. for 5 hours. The mixture waspoured onto ice, neutralized with solid NaHCO₃ and extracted with ethylacetate (x3). The combined organic layers were dried over MgSO₄,filtered and evaporated to dryness. The crude compound was purified byflash chromatography with ethyl acetate 50%-heptane 50% to afford 1.27 gof the title compound as a yellow solid. LCMS Method 3 basic (ES+) RT2.75 min. 492.1 (M+H)+.

INTERMEDIATE 118

(7R,14R)-11-chloro-1-(difluoromethoxy)-5-methyl-7,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

A solution of Intermediate 117 (0.48 g, 0.976 mmol) in dichloromethane(10 mL) was cooled to 0° C. and trifluoroacetic acid (10 mL) was addeddropwise. The reaction mixture was stirred overnight at roomtemperature. The mixture was poured on ice, brought to neutral pH withsolid NaHCO₃ and extracted with dichloromethane (x3). The combinedorganic layers were dried over MgSO₄, filtered and concentrated in vacuoto afford 0.25 g (65%) of the title compound. LCMS basic Method 3 (ES+)RT 2.42 min., 374.1 (M+H)⁺.

INTERMEDIATE 119

(7R,14R)-11-chloro-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

To a solution of Intermediate 118 (350 mg, 0.893 mmol) in a mixture ofTHF (8 mL) and EtOH (8 mL) were added macroporous polymer-supportedcyanoborohydride (1.12 g, 4.4 mmol, 4.0 mmol/g loading) and acetic acid(50 μL). The reaction mixture was stirred overnight at room temperature.The reaction mixture was filtered over celite and concentrated in vacuo.The residue was poured onto ice/water and solid NaHCO₃ was added tillpH=9. The aqueous phase was extracted with DCM (x3), the combinedorganic layers dried over MgSO₄, filtered and concentrated to dryness.The crude compound was purified by normal phase chromatography (DCM95%-MeOH 5%) to afford 237 mg (71%) of the title compound as a mixtureof diastereomers. LCMS Method 3 basic (ES+) RT 1.99 min., 376.1 (M+H)⁺.

INTERMEDIATES 120 and 121

(5R,7R,14R)-11-chloro-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

(5S,7R,14R)-11-chloro-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

The title compounds were isolated from Intermediate 119 (0.118 μ) bypurification under SFC conditions on Chiralpak OD-A20 column (50*266,360 mL/min, 25° C., CO₂+20% iPrOH, con: 24 g/l), yielding 37 mg (31%) ofIntermediate 120 (RT 3.65 min) and 40.0 mg (34%) of Intermediate 121 (RT7.57 min) respectively.

Intermediate 120: LCMS Method 4 (ES+) RT 2.18 min., 376.2 (M+H)+.

Intermediate 121: LCMS Method 4 (ES+) RT 2.14 min., 376.2 (M+H)+.

INTERMEDIATE 122

tert-butyl{(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-2 ,3-dihydro-1H-pyrrolo [1,2-a]benzimidazol-3-yl}carbamate

Intermediate 22 (5 g, 8,331 mmol) was suspended in DCM (10 mL) andcooled on an ice bath. Triethylamine (2.6 mL, 18,33 mmol) anddi-tert-butyl dicarbonate (2.2 g, 10.0 mmol) were added. The reactionwas warmed to ambient temperature and stirred overnight. The reactionmixture was quenched by addition of water (10 mL). The aqueous layer wasextracted by DCM (3×10 mL). The combined organic layers were dried overMgSO₄, filtered and concentrated in vacuum. The residue was purifiedover silica gel (eluting with heptane/ethyl acetate 7/3) to afford 5.1 g(87%) of the title compound as a white solid.

LCMS Method 3 (ES+) RT 3.64 min., 700.3/702.3 (M+H)⁺

INTERMEDIATE 123

Ethyl 2-{(1R,3R)-3-[(tert-butoxycarbonyl)amino]-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-2 ,3-dihydro-1H-pyrrolo[1,2-c]benzimidazol-1-yl}-3-(difluoromethoxy)benzoate

Intermediate 122 (5 g, 7.14 mmol), potassium carbonate (1.50 g, 10.71mmol), molecular sieve 4 A° powder (2 μ) anddichloro[bis(dicyclohexylphosphino)propane]-palladium(II) (350 mg, 0.57mmol) were suspended in dry dimethyl sulfoxide (50 mL) and ethanol (1.8mL, 32 mmol). The slurry was stirred under 5 bars of CO gas at 100° C.,overnight. The slurry was filtered through a pad of celite and rinsedwith ethyl acetate (30 mL). The filtrate was washed successively by asaturated solution of aqueous NH₄Cl (20 mL), brine (20 mL), dried overMgSO₄, filtetred and concentrated in vacuum affording 5.1 gof the crudetitle compound as a brown solid, used without further purification. LCMSMethod 3 (ES+) RT 3.64 min., 738.1 (M+H)⁺.

INTERMEDIATE 124

tert-butyl{(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-(difluoromethoxy)-6-(hydroxymethyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2a]benzimidazol-3-yl}carbamate

Intermediate 123 6 (3 μ) was dissolved in ethanol (30 mL). At 0° C.,sodium borohydride (1.2 μ) was added, followed by calcium chloride(1.805 μ). The reaction mixture was warmed to room temperature andstirred for 4 hours. The reaction mixture was filtered through a pad ofcelite, and rinsed with ethyl acetate (2×20 mL). The filtrate was washedwith water (2×20 mL) and brine (20 mL), and dried over MgSO₄. Theresidue was purified by basic reverse phase preparative HPLC yielding948 mg (33%) of the title compound as a white solid. LCMS Method 3 (ES+)RT 3.45 minutes 696.3 (M+H)⁺.

INTERMEDITE 125

tert-butyl{(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-(difluoromethoxy)-6-formylphenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

Intermediate 124 (750 mg, 1.08 mmol) was dissolved in 1,4-dioxane (16mL) before addition of manganese dioxide (2.3 g, 27 mmol) at roomtemperature. The reaction was stirred overnight. The crude reactionmixture was filtered through a pad of celite and rinsed with 20 mL ofchloroform. The filtrate was concentrated to dryness in vacuum yieldingto a crude 860 mg of title compound used without further purification.LCMS Method 3 basic (ES+) RT 5.85 minutes. 694.4 (M+H)⁺.

INTERMEDIATE 126

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-7,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

Intermediate 125 (860 mg, 1.24 mmol) was treated in accordance with theprocedure described for the synthesis of Intermediate 118 to afford 710mg (99%) of the title compound as a yellow glass.

LCMS Method 3 basic (ES+) RT 5.76 min., 576.2 (M+H)⁺.

INTERMEDIATE 127

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

Intermediate 126 (710 mg, 1.23 mmol) was treated in accordance with thesynthetic method described for Intermediate 119 to afford the titlecompound 655 mg (92%) as a yellow oil.

LCMS Method 3 basic (ES+) RT 5.84 min., 578.7 (M+H)⁺.

INTERMEDIATE 128

1-[(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

To a solution of Intermediate 127 (655 mg, 1.13 mmol) in dichloromethane(11 mL) was added successively pyridine (0.28 mL, 3.4 mmol) and aceticanhydride (0.22 mL, 2.27 mmol). The reaction mixture was stirred at roomtemperature for 90 minutes. The reaction mixture was washed by asaturated aqueous solution of NH₄Cl (2×20 mL) and a saturated aqueoussolution of NaHCO₃ (2×10 mL). The aqueous phases were extracted by DCM(2×10 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated under vacuum. The residue was purified bychromatography over silica gel (eluting with ethyl acetate 100% to ethylacetate/ethanol 9/1), yielding to 300 mg (43%) of title compound as ayellow glass.

LCMS Method 3 basic (ES+) RT 5.84 min., 620.3 (M+H)⁺

INTERMEDIATE 129

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

Intermediate 127 (30 mg, 0.051 mmol) in 2,2,2-trifluoroethanol (3 mL)and formaldehyde (1 mL, 25.97 mmol) was stirred at room temperature for30 minutes before addition of sodium borohydride (20 mg, 0.52 mmol). Thereaction mixture was heated at 70° C. for 2 hours. At room temperature,additional sodium borohydride (20 mg, 0.52 mmol) was added, and thereaction mixture heated at 70° C. for addition 1 hour. The reactionmixture was filtered through a pad of celite, and the residual solidwashed by 2,2,2-trifluoroethanol (2×4 mL). The filtrate was concentratedin vacuum. The residue was used without further purification. LCMSMethod 3 basic (ES+) RT 5.97 min., 592.2 (M+H)+.

INTERMEDIATE 130

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

To a solution of Intermediate 126 (0.074 mmol) in acetonitrile (1 mL)and N,N dimethylformamide (17 μl) was added successively at 0° C.,trifluoroacetic acid (7 μL, 0.092 mmol), potassium hydrogen fluoride(4.4 mg, 0.055 mmol) and (trifluoromethyl)trimethylsilane (16 μL, 0.11mmol). The resulting slurry was allowed to warm to ambient temperatureovernight. The reaction mixture was then evaporated and purified bypreparative basic reverse phase HPLC. This was followed by a secondacidic preparative HPLC to afford the TFA salt of the title compoundwhich was solubilized in EtOAc (2 mL) and washed with a saturatedsolution of NaHCO₃. The aqueous layer was extracted with EtOAc (2×2 mL).The combined organic layers were dried over magnesium sulphate, filteredand concentrated in vacuo to afford 7 mg (15%) of the title compound asa mixture of diastereoisomers.

LCMS Method 3 (ES+) RT 6.08 min., 646.2 (M+H)⁺.

INTERMEDIATE 131 and INTERMEDIATE 132

(5R,7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocineand(5S,7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

To a solution of Intermediate 126 (0.72 mmol) in acetonitrile (5 mL) andDMF (166 μL) was added successively at 0° C., trifluoroacetic acid (69μL, 0.90 mmol), potassium hydrogen fluoride (43 mg, 0.54 mmol) and(trifluoromethyl)trimethylsilane (159 μL, 1.08 mmol). The resultingslurry was allowed to warm to room temperature for 3 hours. The reactionmixture was then diluted with EtOAc and a saturated aqueous solution ofNaHCO₃. The two phases were separated and the aqueous layer furtherextracted with EtOAc (x2). The combined organic extracts were dried overmagnesium sulphate, filtered and concentrated under reduced pressure.

The crude was purified over silica gel (eluting withdichloromethane-methanol-aqueous ammonia/97:2.7:0.3). This was followedby a second purification by reverse phase preparative HPLC to give thefollowing diastereoisomers:

4.8 mg (1%) of Intermediate 131:

LCMS Method 3 (ES+) RT 3.65 min., 646.2 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.72 (m, 2H), 7.19 (m, 1H), 7.05 (s, 2H), 7.00(m, 1H), 6.85 (m, 2H), 6.35 (m, 1H), 5.33 (m, 1H), 4.52 (d, 1H, J=7.0Hz), 3.48 (m, 1H), 2.83 (m, 1H), 2.42 (m, 1H), 1.67 (s, 6H), 0.87 (s,9H), -0.07 (d, 6H, J=1.2 Hz).

2.8 mg (5%) of Intermediate 132:

LCMS Method 3 (ES+) RT 3.66 min., 646.2 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.93 (m, 2H), 7.94 (m, 1H), 7.53 (m, 2H), 7.31(m, 2H), 7.23 (m, 1H), 6.76 (m, 1H), 6.32 (m, 1H), 4.88 (m, 1H), 3.39(m, 1H), 3.19 (m, 1H), 2.67 (m, 1H), 2.54 (m, 1H), 1.70 (s, 6H), 0.89(s, 9H), -0.04 (s, 6H)

INTERMEDIATE 1331-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-3-(trifluoromethyl)azetidin-3-ol

1-(5-bromo-4-methyl-pyrimidin-2-yl)-3-(trifluoromethyl)azetidin-3-ol(700 mg, 2.24 mmol), bis(pinacolato)diboron (1.15 g, 4.49 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (92 mg, 0.112 mmol), potassium acetate (890 mg,8.97 mmol) and 1,4-dioxane (10 mL) were placed in a small RB flask,degassed and placed under nitrogen. The mixture was then heated at 105°C. for 2 hours. The mixture was cooled and partitioned between EtOAc andwater. The organic layer was dried over Na₂SO₄, filtered and evaporatedin vacuo to give the title compound as a dark brown solid 1.60g. LC/MSMethod 3: RT 1.93 minutes, m/z 360.

INTERMEDIATE 1341-(5-bromo-6-methyl-2-pyridyl)-3-(trifluoromethyl)azetidin-3-ol

2,5-dibromo-6-methylpyridine (1.30 g, 5.18 mmol) and3-(trifluoromethyl)azetidin-3-ol hydrochloride (1.00 g, 5.63 mmol) wereadded to a small RB flask with stirrer bar. N,N-diisopropylethylamine(0.90 mL, 5.2 mmol) was added and the mixture heated to 130° C. for 4hours. The mixture was cooled, diluted with dichloromethane (50 mL) andwashed with sodium bicarbonate solution (50 mL). The organic layer wasdried (Na₂SO₄), filtered and concentrated in vacuo. Chromatography(silica, DCM gradient to 15% EtOAc in DCM) gave the title compound as awhite solid (210 mg, 13.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (d,J=8.7 Hz, 1H), 7.32 (s, 1H), 6.32 (dd, J=8.7, 0.7 Hz, 1H), 4.19 (dd,J=9.6, 1.0 Hz, 2H), 3.93 (dt, J=9.4, 1.3 Hz, 2H), 2.42 (s, 3H).

LC/MS Method 3: RT 2.02 minutes, m/z 313/315.

INTERMEDIATE 1351-[6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)azetidin-3-ol

Intermediate 134 was treated in accordance with the synthetic proceduredescribed for

Intermediate 133 to afford the title compound as pale brown gum whichwas used without further purification. LC/MS Method 3: RT 2.29 minutes,m/z 359.

INTERMEDIATE 136

2-ethylhexyl3-[2-[(1R,3S)-7-chloro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)phenyl]sulfanylpropanoate

N,N-di-iso-propylethylamine (1.63 mL, 9.31 mmol) was added to a solutionof Intermediate 38 (2.00 g, 4.66 mmol) in 1,4-dioxane (10 mL). Themixture was evacuated and refilled with nitrogen. The catalyst,tris(dibenzylideneacetone)dipalladium(0) (213 mg, 0.233 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (275 mg, 0.466 mmol) and3-mercaptopropionic acid 2-ethylhexyl ester (1.86 mL, 7.93 mmol) wereadded and the mixture was evacuated and filled with nitrogen and heatedunder nitrogen at 105° C. for 18 hours. The mixture was partitionedbetween EtOAc (250 mL) and saturated aqueous sodium bicarbonate solution(100 mL). The organic layer was dried (sodium sulfate), filtered andconcentrated in vacuo to leave a yellow oil, 4.00 g. Purification bychromatography (silica, dichloromethane gradient up to 5% methanol indichloromethane) afforded the title product as a pale yellow foam (2.10g, 80% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.62 (dd, J=8.6, 1.9 Hz, 1H),7.54-7.41 (m, 1H), 7.36-7.21 (m, 1H), 7.21-7.09 (m, 1H), 7.06-6.86 (m,1H), 6.74-6.52 (m, 1H), 6.46-6.21 (m, 1H), 6.03 (dd, J=6.7, 3.7 Hz, 1H),5.36-5.07 (m, 1H), 4.05-3.80 (m, 2H), 3.35 (td, J=6.8, 2.6 Hz, 2H),3.25-2.64 (m, 4H), 2.24 (ddt, J=24.0, 16.6, 8.4 Hz, 1H), 1.50 (dd,J=12.5, 6.4 Hz, 1H), 1.37-1.08 (m, 8H), 0.92-0.68 (m, 6H). LC/MS Method3: RT 3.00 minutes, m/z 381/383.

INTERMEDIATE 1371-(5-bromo-4-methyl-2-pyridyl)-3-(trifluoromethypazetidin-3-ol

The title compound was synthesised from 2,5-dibromo-4-methylpyridine and3-(trifluoromethyl)azetidin-3-ol hydrochloride in accordance with thesynthetic procedure described for Intermediate 134.

INTERMEDIATE 1381-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)azetidin-3-ol

Intermediate 137 was treated in accordance with the synthetic proceduredescribed for Intermediate 135 to afford the title compound which wasused without further purification.

INTERMEDIATE 139 Ethyl 5-bromo-4-methylpyrimidine-2-carboxylate

5-bromo-4-methylpyrimidine-2-carboxylic acid (17.8 g, 82 mmol) dissolvedin ethanol (185 mL). Sulfuric acid (38.6 g, 394 mmol, 21 mL) was addedand the resulting suspension was placed in a preheated oil bath of 80°C. Additional sulfuric acid (3.68 g, 37.5 mmol, 2 mL) added and heatingcontinued for a further hour before cooling to room temperature. Thesolid was filtered and residue washed with EtOH. The filtrate wasevaporated and the residue taken up in EtOAc (300 mL) and sat. aqueousNaHCO₃ solution (300 mL). The layers were separated and the aqueousphase extracted with EtOAc (300 mL). The combined organics were washedwith brine (300 mL), dried (Na₂SO₄), filtered and evaporated to give adark solid which was purified by column chromatography 300 gsilica(20%->50% EtOAc in heptane) to give the title compound as a yellow solid(12.24 g, 44%). ¹H NMR (300 MHz, Chloroform-d) δ 8.87 (s, 1H), 4.53 (q,J=7.1 Hz, 2H), 2.76 (s, 3H), 1.46 (t, J=7.1 Hz, 3H). LC/MS Method 11 RT1.57 minutes, [M+H]⁺: 245/247 Br-isotope.

INTERMEDIATE 140 2-(5-bromo-4-methylpyrimidin-2-yl)propan-2-ol

Under a nitrogen atmosphere methyl magnesium bromide solution (3M inEt₂O 109 mmol, 36.4 ml) was added dropwise to a stirred mixture ofIntermediate 139 (10.7 g, 43.7 mmol) in diethyl ether (300 mL) whilecooled in an ice/water bath. During addition a suspension formed. Whenaddition was completed the mixture was stirred at room temperature. Thereaction mixture was carefully quenched with saturated aqueous NH₄Clsolution (300 mL). The resulting organic layer was separated and theaqueous phase was extracted with Et₂O (300 mL). The combined organicswere washed with brine, dried (Na₂SO₄), filtered and evaporated todryness to give an orange oil.

Purification by flash chromatography (300 gsilica, 10%->50% EtOAc inheptane) gave the title compound as a light yellow oil (7.5 g, 74%). ¹HNMR (300 MHz, Chloroform-d) δ 8.67 (s, 1H), 4.51 (s, 1H), 2.65 (s, 3H),1.58 (s, 6H). LC/MS Method 9: [M+H]⁺231/233 Br-isotope.

INTERMEDIATE 141

(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-(difluoromethoxy)-6-(methylsulfanyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

To a solution of Intermediate 22 (415 mg, 0.69 mmol) in DMSO (2 mL) wasadded sodium thiomethoxide (64 mg, 0.83 mmol). The reaction mixture wasstirred for 25 minutes at 100° C. Water (20 mL) and ethyl acetate (40mL) were added to the reaction mixture, and the two layers wereseparated. The aqueous layer was extracted with ethyl acetate (2×40 mL)and the combined organics layers were dried over MgSO₄, filtered andconcentrated in vacuo. The crude material was purified over silica gelusing DCM/MeOH/NH₄OH (100% DCM to 90/10/1) as eluent, yielding 310 mg(73%) of the title compound as a brown solid. LCMS Method 3 (ES+): RT2.72 min, [M+H]+=612.2

INTERMEDIATE 142

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-methyl-7,14-dihydro-7,14-methano-5λ-4-benzimidazo[2,1-d][1,2,5]benzothiadiazocine5-oxide

To a degassed solution of Intermediate 141 (87 mg, 0.14 mmol) in MeOH (5mL) was added a solution of bromine (19 mg, 0.12 mmol) in MeOH (0.5 mL).The reaction mixture was evaporated after 1 hour and the residue wassolubilised in DCM (5 mL). The solution was degassed by bubbling ofargon through the solution for 5 minutes. Potassium carbonate (63 mg,0.45 mmol) and 3-chloroperbenzoIc acid (74 mg, 0.43 mmol) were thenadded to the mixture. The mixture was stirred overnight at ambienttemperature before dilution with DCM (40 mL) and the organic layerwashed with water (2×20 mL), dried by passage through a phase separatorcartridge and concentrated in vacuo. The crude material was purifiedover silica gel using DCM/MeOH/NH₄OH (100% DCM to 90/10/1) as eluent,yielding 8 mg (9%) of the title compound as a dark oil. LCMS Method 3(ES⁺): RT 3.27 minutes, [M+H]+=626.2.

INTERMEDIATE 143 5-bromo-2-(1-methylsulfonylcyclopropyl)pyridine

5-bromo-2-[(methylsulfonyl)methyl]pyridine (300 mg, 1.20 mmol),1,2-dibromoethane (0.12 mL, 1.40 mmol), benzyltributylammonium chloride(377 mg, 1.20 mmol) and sodium hydroxide 50% aqueous solution (7.5 mL,94 mmol) were mixed in acetonitrile (8 mL). The reaction mixture wasstirred at room temperature for 24 hours. Aqueous saturated NaClsolution and ethyl acetate were added to the reaction mixture and thetwo layers were separated. The organic layer was dried over MgSO₄,filtered and the solvent evaporated. The crude was purified by reversephase basic preparative LCMS to yield 32 mg (10%) of the title compoundas an off-white solid. LCMS Method 3 (ES+): RT 1.86min, [M+H]+=276.

INTERMEDIATE 144

(1 R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]benzimidazol-3-one

To a solution of Intermediate 19 (3 g, 6.98 mmol) in chloroform (60 mL),was added manganese dioxide (3.64 g, 42 mmol) and the reaction mixturewas stirred at room temperature for 3 hours, after which additionalmanganese dioxide (2 g, 23 mmol) was added and stirred overnight. Thereaction mixture was filtered over celite, rinsed with chloroform (2×60mL) and the filtrate concentrated in vacuo to yield 2.91 g(97%) of thetitle compound as a beige solid. LCMS Method 3 (ES+): RT 4,88 min,[M+H]+=427.

INTERMEDIATE 145

N-{(1R,3E)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]benzimidazol-3-ylidene}-2-methylpropane-2-sulfinamide

Titanium(IV) isopropoxide (1,86 mL, 9.52 mmol) was added to a solutionof Intermediate 144 (1.85 g, 4.33 mmol) in dry THF (43 mL). The mixturewas stirred at room temperature for 10 minutes before addition of(R)-(+)-2-methyl-2-propanesulfinamide (642 mg, 5.2 mmol). The reactionmixture was stirred at 50° C. overnight. Further(R)-(+)-2-methyl-2-propanesulfinamide (320 mg, 2.58 mmol) was added andthe reaction mixture stirred at 50° C. overnight. The reaction mixturewas cooled to 0° C. and methanol was added followed by a saturatedaqueous solution of NaHCO₃ until precipitation was observed. The slurrywas diluted by EtOAc (50 mL) and filtered over celite. The filtrate waswashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified over silica gel (gradient EtOAc/heptane20 to50%) yielding 770 mg (34%) of the title compound as a brown solid.LCMS Method 3 (ES+): RT 2.82 min, [M+H]⁺=530.

INTERMEDIATE 146

N-{(1R,3R)-1-[2-bromo-6-(difluoromthoxy)phenyl]-7-chloro-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}-2-methylpropane-2-sulfinamide

To a solution of Intermediate 145 (8 g, 15.1 mmol) in dry DCM (90 mL),cooled at −70° C., was added dropwise a solution of methyl magnesiumbromide 3 M in diethyl ether (17.6 mL, 52.8 mmol). The reaction mixturewas stirred at −70° C. for 10 minutes and at 0° C. for 2 hours beforequenching by addition of a saturated solution of NH₄Cl (100 mL). Theaqueous layer was extracted with DCM (2×100 mL). The combined organiclayers were washed with saturated brine and dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified over silica gel(gradient ethyl heptane/acetate 50 to 100%), yielding to 2.91 g(35%) ofthe title compound as a beige solid. LCMS Method 3 (ES+): RT 2.68 min,[M+H]⁺=546.10

INTERMEDIATE 147

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

Intermediate 146 (2.91 g, 5.32 mmol) was dissolved in dry 1,4-dioxane(150 mL). HCl/dioxane (4M) (6.65 mL, 27 mmol) was added and the reactionmixture was stirred at room temperature for 4 hours. The solvent wasevaporated and the residue was taken up in EtOAc (50 mL) and a saturatedaqueous solution of NaHCO₃ (20 mL) added. The organic layer was washedwith saturated brine, dried over MgSO₄, filtered and concentrated invacuo. The residue was dissolved in diethyl ether and evaporatedyielding to 2.2 g(93%) of the title compound as a yellow solid. LCMSMethod 3 (ES+): RT 2.43 min, [M+H]⁺=442.1.

INTERMEDIATE 148

(7R,14R)-11-chloro-1-(difluoromethoxy)-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 147 (50 mg, 0.11 mmol), potassium carbonate (23 mg, 0.170mmol),dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II)(4 mg, 0.006 mmol) were mixed in degassed 1,4-dioxane (2 mL). Themixture was stirred under CO gas (3 bar) at 120° C. for 4 hours.Additional bis(diphenylphosphino)xanthene]palladium(II) (4 mg, 0.006mmol) was introduced in the reactor at room temperature and the reactioncontinued under stirring under CO (3 bar) at 120° C. for 16 hours. Thecrude mixture was purified over silica gel (ethyl acetate as eluent),yielding 71 mg (37%) of the title compound as an off-white solid. LCMSMethod 3 (ES+): RT 2.34 min, [M+H]+=390.

INTERMEDIATE 149

(7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 148 (80 mg, 0.21 mmol) and tetrabutylammonium iodide (30mg, 0.08 mmol) were mixed in dry THF (2 mL). At 0° C., sodium hydride(60% in mineral oil) (9 mg, 0.246 mmol) was added. The reaction mixturewas stirred at room temperature for 35 minutes. Iodomethane (0.08 mL,1.24 mmol) was added and the reaction mixture was stirred at ambienttemperature overnight. The reaction mixture was quenched by addition ofwater (1 mL). The aqueous layer was extracted by EtOAc (3×2 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified over silica gel (heptane/DCM 50% to100%), yielding 60 mg (72%) of the title compound as a white solid. LCMSMethod 4 (ES+): RT 2.63 min, [M+H]⁺404.

INTERMEDIATE 150

tert-butyl(2-{5-[(7R,14R)-1-(difluoromethoxy)-7-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

tert-butyl N-[1-(5-bromopyrimidin-2-yl)-1-methyl-ethyl]carbamate (36 mg,0.11 mmol), bis(pinacolato)diboron (36 mg, 0.14 mmol), potassium acetate(11 mg, 0.12 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 0.008mmol), were mixed in dioxane (3 mL). The reaction mixture was stirred at100° C. for 2 hours. The reaction mixture was filtered through a 45 μMfilter, and concentrated in vacuo. The residue was dissolved inn-butanol (5 mL) and Intermediate 148 (15 mg, 0.038 mmol),tricyclohexylphosphonium tetrafluoroborate (4 mg, 0.009 mmol),tris(dibenzenylideneacetone)dipaladium(0) (4 mg, 0.0038 mmol), potassiumtriphosphate (17 mg, 0.077 mmol) and water (50 μL) were added. Thereaction mixture was stirred at 140° C. in a microwave for 25 minutes.The reaction mixture was filtered and purified by reverse phase basicpreparative HPLC-MS to yield 13 mg (57%) of the title compound as abeige solid. LCMS Method 3 (ES+): RT 2.42 minutes, [M+H]⁺=591.

INTERMEDIATE 151

(1R,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

To a solution of Intermediate 21 (2 g, 3.33 mmol) in DMF (12 mL) wasadded imidazole (283 mg, 4.16 mmol) and tert-butyldimethylchlorosilane(543 mg, 3.49 mmol) and the reaction mixture was stirred overnight atroom temperature. The reaction was then diluted with diethyl ether (30mL) and water (30 mL). The aqueous layer was extracted with diethylether (2×20 mL). The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure toafford the title compound which was used in the next step withoutfurther purification. LCMS Method 3 (ES+): RT 7.09 min.

INTERMEDIATE 152

Ethyl2-{(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}-3-(difluoromethoxy)benzoate

Intermediate 151 (2.05 g, 2.87 mmol), potassium carbonate (1.5 equiv.,4.30 mmol), molecular sieve 4A powder (860 mg) anddichloro[bis(dicyclohexylphosphino)propane]palladium(II) (0.08 equiv.,0.23 mmol) were suspended in dry dimethylsulfoxide (20 mL) and ethanol(0.75 mL). The reaction mixture was stirred at 100° C. under 5 bars ofCO gas for 16 hours. After this time, another portion ofdichloro[bis(dicyclohexylphosphino)propane]palladium(II) was added andthe reaction stirred overnight at 100° C. under 5 bars of CO gas tocomplete the reaction. The reaction mixture was allowed to cool toambient temperature, filtered over celite and partitioned between EtOAc(50 mL) and water (50 mL). The organic layer was washed with water (2×20mL), dried over MgSO₄, filtered and concentrated under reduced pressure.The residue was purified over silica gel (DCM:MeOH 99.5%:0.5%), yielding824 mg (38%) of the title compound. LCMS Method 3 (ES+): RT 3.92 min,753 (M+H)⁺.

INTERMEDIATE 153

[2-{(1R,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}-3-(difluoromethoxy)phenyl]methanol

Intermediate 152 (780 mg, 1.04 mmol) was dissolved in dry ethanol (8mL). At 0° C., sodium borohydride (317 mg, 8.30 mmol) followed bycalcium chloride (460 mg, 4.15 mmol) were added . The reaction wasallowed to warm to ambient temperature and stirred for 4 hours. Thereaction was then diluted with EtOAc (20 mL) and water (10 mL). Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified oversilica gel (hexane:ethyl acetate 80 : 20), yielding 233 mg (32%) of thetitle compound. LCMS Method 3 (ES+): RT 3.69 min, 711 (M+H)⁺.

INTERMEDIATE 154

2-{(1R,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazo1-1-yl}-3-(difluoromethoxy)b enzaldehyde

Intermediate 153 (233 mg, 0.33 mmol) was dissolved in DCM (5 mL) beforethe addition of Dess-Martin periodinane (157 mg, 0.36 mmol). The slurrywas stirred overnight at ambient temperature. Additional Dess-Martinperiodinane (72 mg, 0.16 mmol) was added and the reaction mixture wasstirred at room temperature for 3 hours to complete the reaction. Theslurry was filtered and the filtrate was diluted with DCM (20 mL) andwashed by a saturated aqueous solution of NaHCO₃ (10 mL). The aqueouslayer was extracted with DCM (2×10 mL). The combined organic layers weredried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified over silica gel (hexane:ethyl acetate 80:20),yielding 190 mg (82%) of the title compound. LCMS Method 3 (ES+): RT3.79 min, 709 (M+H)⁺.

INTERMEDIATE 155

(1R,3S)-1-[2-(difluoromethoxy)-6-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

Intermediate 154 (190 mg, 0.27 mmol) was dissolved in tetrahydrofuran (3mL). At 0° C., tetrabutylammonium fluoride (54 μL, 0.054 mmol) followedby (trifluoromethyl)trimethylsilane (79 μL, 0.54 mmol) were added. Thereaction was allowed to warm to room temperature and stirred for 2hours. The reaction was then diluted with EtOAc (10 mL) and water (5mL). The aqueous layer was extracted with further EtOAc (2×5 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was dissolved in methanol (1 ml) andp-toluenesulfonic acid monohydrate (255 mg, 1.34 mmol) was added. Thereaction was stirred overnight at room temperature. Additionalp-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) was added and thereaction mixture was stirred at ambient temperature overnight tocomplete the reaction. The reaction mixture was diluted with EtOAc (10mL) and a saturated aqueous solution of NaHCO₃ (5 mL). The aqueous layerwas extracted with EtOAc (2×5 mL). The combined organic layers weredried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by reverse phase basic preparative HPLC-MS toafford 97 mg (66%) of the title compound as a white solid. LCMS Method 3(ES+): RT 2.03 min, 551 (M+H)⁺.

INTERMEDIATE 156

(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-3-amine

To a solution of Intermediate 72 (212 mg, 0.42 mmol) and4-dimethylaminopyridine (4 mg, 0.033 mmol) in DCM (4 mL) at 0° C. wasadded N,N-di-isopropylethylamine (441 μL, 2.52 mmol), followed bytert-butyldimethylsilyl-trifluoromethanesulfonate (395 μL, 1.69 mmol).The reaction mixture was stirred at 0° C. for 20 minutes before thecooling bath was removed and the reaction mixture was allowed to warm upto room temperature. After 45 minutes the reaction mixture was dilutedwith DCM (100 mL) and washed with water (2×50 mL), brine (50 mL), dried(by passage through a phase separator cartridge) and concentrated invacuo. The crude material was purified by column chromatography (SiO₂,60-100% EtOAc in hexane, followed by 0-25% MeOH in EtOAc) and freezedried from acetonitrile/water to give the title compound (190 mg, 73%)as an off-white solid. LCMS Method 3 (ES+) 618 (M+H)⁺, RT 3.44 minutes.LCMS Method 4 (ES+) 618 (M+H)⁺, RT 3.04 minutes.

INTERMEDIATE 157

(6R,12R)-2-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanopyrido[1′,2′:1,2]imidazo[4,5-c][1]benzazepine

To a microwave vial was added tris(dibenzylideneacetone)dipalladium(0)(9.5 mg, 0.01 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10.2 mg, 0.021mmol), followed by degassed 1,4-dioxane (2 mL), and the microwave vialthen sealed and degassed and stirred at room temperature for 30 minutes.After this time Intermediate 156 (125 mg, 0.20 mmol) and sodiumtert-butoxide (41 mg, 0.40 mmol) then added and reaction mixturedegassed and heated to 110° C. for 18 hours. The reaction mixture waspartitioned between EtOAc (25 mL) and water (25 mL), the layersseparated and aqueous extracted with EtOAc (25 mL). The combinedorganics were washed with brine (25 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The crude material was purified by columnchromatography (SiO₂, 0-20% MeOH in DCM) to give the title compound (69mg, 59%) as a dark brown glass.

-   -   ¹H NMR (300 MHz, Methanol-d₄) δ 8.95 (d, J=1.6 Hz, 2H), 8.37 (d,        J=7.3 Hz, 1H), 7.38 (d, J=11.2 Hz, 1H), 6.96 (t, J=75 Hz, 1H),        6.88 (t, J=8.1 Hz, 1H), 6.40-6.26 (m, 2H), 4.89-4.73 (m, 2H)        3.45-3.32 (m, 1H), 2.21 (d, J=10.5 Hz, 1H), 1.73 (s, 6H), 0.91        (s, 9H), -0.01 (s, 6H).

LCMS: Method 3 (ES+) 582 (M+H)⁺, RT 3.39 minutes.

LCMS Method 4 (ES+) 582 (M+H)⁺, RT 3.48 minutes.

INTERMEDIATE 159

(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of Intermediate 110 (2.01 g, 5.12 mmol) in 1,4-dioxane (18mL) was added bis-(pinacolato)diboron (1.97 g, 7.8 mmol), potassiumacetate, (1.5 g, 15.1 mmol), tricyclohexylphosphonium tetrafluoroborate(197 mg, 0.15 mmol) and tris(dibenzylideneacetone)dipalladium(0) (242mg, 0.25 mmol). The reaction mixture was degassed for 10 minutes beforeheating to 140° C. in the microwave for 3 hours. Water and EtOAc wasadded to the reaction mixture and the aqueous phase extracted withfurther EtOAc. The combined organic layers were evaporated to give acrude residue which was purified by column chromatography on silica(eluent Hexane:EtOAc gradient from 0 to 100% followed by DCM:MeOH to 10%MeOH) to provide the title compound as a white solid (2.2 g, 89% yield).LC/MS: Method 3 RT 2.27 mins, [M+H]⁺=485.

INTERMEDIATE 160

(7R,14R)-11-[2-(cis-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-3-methylcyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2.5]benzodiazocin-5(14H)-one

Intermediate 159 (401 mg, 0.83 mmol) and Intermediate 79 (403 mg, 1.08mmol) in 1,4-dioxane (10 mL) were degassed,1,1′-bis(diphenylphospino)ferrocene-palladium(II)dichloridedichloromethane complex (35 mg, 0.043 mmol) and K₃PO₄ (282 mg, 1.33mmol) were added and reaction mixture degassed and then heated at 110°C. for 18 hours, or until LCMS analysis showed the reaction to becompleted. The reaction mixture was allowed to cool to room temperature,partitioned between EtOAc (20 mL) and saturated aqueous sodiumbicarbonate solution (20 mL), the layers were separated and the aqueousphase extracted with further EtOAc (3×25 mL). The combined organics weredried over sodium sulphate, filtered and concentrated in vacuo. Thecrude material was purified by column chromatography (SiO₂, 0-100% EtOAcin hexane, followed by 0-15% MeOH in DCM) to give the title compound(221 mg, 41%) as a yellow foam.

¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (s, 2H), 8.27 (dd, J=5.9, 3.6 Hz, 1H),7.78 (d, J=8.5 Hz, 2H), 7.69 (t, J=73.6 Hz, 1H), 7.65 (dd, J=8.3, 1.8Hz, 1H), 7.52-7.44 (m, 2H), 6.31 (d, J=7.2 Hz, 1H), 5.25 (d, J=6.9 Hz,1H), 5.03 (s, 1H), 3.58-3.45 (m, 1H), 3.10-3.02 (m, 1H), 2.84 (d, J=13.6Hz, 1H), 2.56-2.45 (m, 2H), 2.48-2.40 (m, 1H), 0.93 (s, 3H), 0.80 (s,6H), -0.19 (d, J=1.4 Hz, 9H).

LCMS: Method 3 (ES+) 651 (M+H)⁺, RT 2.51 minutes.

INTERMEDIATE 161

Ethyl2-[2-[(1R,3S)-7-chloro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)phenyl]sulfanylacetate

The title compound was prepared from Intermediate 38 (2.02 g, 4.7 mmol),N,N-di-iso-propylethylamine (1.63 mL, 9.31 mmol),tris(dibenzylideneacetone)dipalladium(0) (213 mg, 0.23 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (275 mg, 0.47 mmol) andethyl thioglycolate (980 mg, 7.99 mmol) by the method of Intermediate136. Crude material was purified by column chromatography (SiO₂, 20-100%EtOAc in hexane) to give the title compound (1.76 g, 80%) as a yellowsolid.

LCMS: Method 3 (ES+) 469 (M+H)⁺, RT 2.08 minutes.

LCMS: Method 4 (ES+) 469 (M+H)⁺, RT 2.05 minutes.

INTERMEDIATE 162

Ethyl(7S,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate5,5-dioxide INTERMEDIATE 163

Ethyl(7R,14S)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate5-oxide

To a solution of Example 115 (150 mg, 0.33 mmol) in DCM (5 mL) was added3-chloroperoxybenzoic acid (149 mg, 0.66 mmol). The reaction mixture wasstirred at room temperature for 18 hours, after which time the reactionmixture was partitioned between DCM (25 mL) and water (25 mL), layersseparated and organics washed with saturated aqueous sodium bicarbonatesolution. The aqueous phase was extracted with DCM (20 mL), the combinedorganics filtered through a phase separator and concentrated in vacuo.The residue was purified by column chromatography (SiO₂, 0-60% EtOAc inDCM) and freeze dried from acetonitrile/water to give Intermediate 162(65 mg, 40%) as an off-white solid and Intermediate 163 (47 mg, 30%) asa white solid.

Intermediate 162

LCMS: Method 3 (ES+) 483 (M+H)⁺, RT 2.12 minutes (minor diastereoisomer)and 2.26 minutes (major diastereoisomer)

LCMS: Method 4 (ES+) 483 (M+H)⁺, RT 2.09 minutes (minor diastereoisomer)and 2.26 minutes (Major diastereoisomer).

Intermediate 163

LCMS: Method 3 (ES+) 467 (M+H)⁺, RT 2.22 minutes (major diastereoisomer)

LCMS: Method 4 (ES+) 467 (M+H)⁺, RT 2.20 minutes (Majordiastereoisomer).

INTERMEDIATE 164

2-[(7S,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-6-yl]propan-2-ol

To a solution of Example 115 (98 mg, 0.22 mmol) in THF (5 mL) at 0° C.was added methylmagnesium bromide (3M in diethylether, 0.16 mL, 0.48mmol). The reaction mixture was allowed to warm to room temperature andstirred for 18 hours. After this time the reaction was quenched withmethanol, concentrated in vacuo and the residue partitioned betweenEtOAc (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL),the layers separated and the aqueous phase extracted with EtOAc (3×30mL), the combined organics were washed with brine (60 mL), dried(MgSO₄), filtered and concentrated in vacuo. Purification by columnchromatography (SiO₂, 0-20% MeOH in DCM) and freeze drying fromacetonitrile/water gave the title compound (28 mg, 29%).

LCMS: Method 3 (ES+) 437 (M+H)⁺, RT 2.44 minutes.

LCMS: Method 4 (ES+) 437 (M+H)⁺, RT 2.38 minutes.

INTERMEDIATE 165

[(7S,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-6-yl]methanol

To a solution of Example 115 (88 mg, 0.15 mmol) in THF (1.5 mL) at -10°C. was added lithium aluminium hydride (2M solution in THF, 0.1 mL, 0.20mmol). The reaction mixture was stirred below 0° C. for 1 hour afterwhich time the reaction was quenched with a few drops of 2 M HCl,stirred and then basified with 10% NaOH (aq) (20 mL) and extracted withEtOAc (4×25 mL). The combined organic phases were dried (Na₂SO₄),filtered and concentrated in vacuo. Purification by columnchromatography (SiO₂, 50-100% EtOAc in DCM, followed by 0-20% MeOH inEtOAc) and freeze drying from acetonitrile/water gave the title compound(35 mg, 57%) as a white solid. LCMS: Method 3 (ES+) 409 (M+H)⁺, RT 2.18minutes (major diastereoisomer) and 2.22 minutes (minor diastereoisomer)

LCMS: Method 4 (ES+) 409 (M+H)⁺, RT 2.14 minutes.

INTERMEDIATE 166

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-trimethylsilyloxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 11 (750 mg, 2.00 mmol),6-(2-(trimethylsilyloxy)propan-2-yl)pyridine-3-boronic acid pinacolester (1.41 g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (94mg, 0.1 mmol) and tricyclohexylphosphonium tetrafluoroborate (91 mg,0.24 mmol, 97 mass%) were added to a round bottom flask, evacuated &refilled with nitrogen and 1,4-dioxane (10 mL) added followed bypotassium phosphate (1.27 g, 6.00 mmol) in water (1 mL). The mixture wasdegassed, placed under nitrogen and heated to 105° C. overnight. Themixture was partitioned between EtOAc and water, the organic layer driedover sodium sulphate, filtered and concentrated in vacuo. The crudematerial was purified by chromatography, (EtOAc to 15% MeOH gradient).The product fractions were concentrated in vacuo to give the titlecompound as an off-white solid, (1.05 g, 96% yield). LC/MS Method 3: RT1.61 minutes, m/z 549.

INTERMEDIATE 167 tert-Butyl3-(5-bromo-2-pyridyl)-3-hydroxy-pyrrolidine-1-carboxylate

2,5-dibromopyridine (2.00 g, 8.27 mmol) was dissolved in toluene (40mL), cooled to −78° C. and n-butyllithium (7.1 mL, 9.9 mmol, 1.40 M)solution in n-hexane added dropwise and stirred for 10 minutes beforethe addition of N-BOC-3-pyrrolidinone (1.61 g, 8.69 mmol) in toluene (3mL). The mixture was stirred at −60° C. for 1 hour, quenched withmethanol (2 mL) and partitioned between EtOAc and saturated aqueousammonium chloride solution. The organic layer was concentrated in vacuoto yield a crude residue. Purification by chromatography (silica, 0 to60% EtOAc gradient in iso-hexane) gave the title compound as anoff-white solid (1.05 g, 3.06 mmol, 37% yield). ¹H NMR (300 MHz,DMSO-d₆) δ 8.65 (dd, J=2.5, 0.7 Hz, 1H), 8.07 (dd, J=8.5, 2.4 Hz, 1H),7.66 (d, J=8.5 Hz, 1H), 5.76 (s, 1H), 3.63 (t, J=11.3 Hz, 1H), 3.56-3.37(m, 4H), 2.43-2.21 (m, 1H), 1.98-1.86 (m, 1H), 1.41 (s, 9H). LC/MSMethod 3: RT 1.57 minutes, m/z 341/343 (-ve ion).

INTERMEDIATE 168 MethylN-[1-(5-bromopyrimidin-2-yl)-1-methyl-ethyl]carbamate

To a cooled (0° C.) solution of 2-(5-bromopyrimidin-2-yl)propan-2-amine(2 g, 9.25 mmol) in dichloromethane (50 mL) was addedN,N-diisopropylethylamine (2.2 equiv., 20.3 mmol) followed by methylchloroformate (1 equiv., 9.25 mmol) and the mixture stirred at roomtemperature for 4 hours. The dichloromethane solution was extracted with2M HCl (x2) washed with saturated aqueous sodium bicarbonate solution,dried over sodium sulphate, filtered and the solvents removed in vacuoto give 2.6 gof a pale reddish solid which was used without furtherpurification.

LCMS Method 3 RT =1.15 minutes

INTERMEDIATE 169

1-[2-[(1R,3S)-3-bromo-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoro methoxy)phenyl]ethanone

Intermediate 181 (58.0 mg, 0.148 mmol) and triphenylphosphine (43.0 mg,0.162 mmol) were dissolved in DCM (2 mL), and at 0° C. was added carbontetrabromide (54.0 mg, 0.163 mmol). The reaction mixture was warmed upto ambient temperature and stirred for 3 hours, partitioned betweenwater and DCM, and the organics, dried (MgSO₄), filtered andconcentrated in vacuo. The crude material was purified by columnchromatography (0%-5% MeOH in DCM) to afford the title compound (74 mg,77%). LC/MS: Method 3 ESI MFI⁺455/457, retention time 2.18 minutes.

INTERMEDIATE 170 2-(5-bromopyrimidin-2-yl)-N,N-dimethyl-propan-2-amine

To a solution of 1-(5-bromopyrimidin-2-yl)-1-methylethylamine (500 mg,2.20 mmol) in THF (15 mL) was added sodium hydride (97 mg, 2.43 mmol) at0° C. The reaction mixture was stirred at 0° C. for 15 min before theaddition of iodomethane (0.17 mL, 2.64 mmol) dropwise. The mixture wasstirred at 0° C. for 30 mins before warming to room temperature andstirred for 16 hours. Iodomethane (0.165 mL, 2.64 mmol) was added andstirred for additional hour before being quenched with saturated aqueousNH₄Cl solution and extracted with DCM (3×10 mL). The organics werecombined, dried with Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by column chromatography (0-5% MeOH in DCM)to give the title compound (120 mg, 22%).

LC/MS: Method 3 retention time 1.23 minutes.

INTERMEDIATE 171

(7R,14R)-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 11 (150 mg, 0.40 mmol) in 1,4-dioxane (1.5 mL) was added tobis(pinacolato)diboron (150 mg, 0.59 mmol), potassium acetate, (117 mg,1.19 mmol), tricyclohexylphosphonium tetrafluoroborate (15 mg, 0.040mmol) and tris(dibenzylideneacetone)dipalladium(0) (19 mg, 0.02 mmol)were added. The reaction mixture was degassed for 10 minutes beforeheating to 140° C. in the microwave for 3 hours. The reaction mixturewas partitioned between EtOAc and water and extracted with further EtOAC(x3). The combined organic phases were filtered through a phaseseparator and the solvents removed in vacuo to give the title compoundwhich was used without further purification. LC/MS: Method 3 RT 2.09mins, [M+H]⁺=468.

INTERMEDIATE 172

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]-6-methoxy-pyridine-3-sulfonamide

To a solution of Intermediate 40 (500 mg, 1.17 mmol) andN,N-di-isopropylethylamine (0.24 mL, 1.4 mmol, 180 mg) indichloromethane (12 mL) was added 6-methoxypyridine-3-sulfonyl chloride(325 mg, 1.52 mmol). The reaction mixture was stirred at roomtemperature for 3 hours before the reaction mixture was concentrated invacuo. The residue was purified by column chromatography (SiO₂, 0-100%EtOAc in hexane) to give the title compound (600 mg, 86%) as a darkbeige solid. LCMS (ES+) Method 3: 600/602 (M+H)⁺, RT 2.4 minutes

INTERMEDIATE 173

2-[(1R,3S)-7-chloro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)benzenesulfonamide

To a solution of Intermediate 136 (1.0 g, 1.67 mmol) in dimethylsulfoxide (2.8 mL), sodium ethoxide solution (3M in EtOH, 1.13 mL, 3.3mmol) was added. The reaction mixture was stirred for 10 minutes beforeadditional sodium ethoxide solution (3M in ethanol, 1.13 mL, 3.3 mmol)was added and the mixture stirred for 5 minutes.Hydroxylamine-O-sulfonic acid (1.0 g, 8.58 mmol,) and sodium acetate(550 mg, 6.70 mmol) in 2 mL of water were added to the reaction mixture.The reaction mixture was stirred overnight at room temperature. EtOAcand water were added to the reaction mixture and the two phases wereseparated. The aqueous layer was extracted with EtOAc and the combinedorganic layers were filtered through a phase separator and the solventwas evaporated. The crude material was purified by column chromatographyover silica gel using hexane/ethyl acetate (0 to 100%) then DCM:MeOH (0to 20%) as eluent, yielding 300 mg (42%) of the title compound as a paleyellow solid. LCMS Method 3: RT 1.57 min, [M−H]⁺=430/432.

INTERMEDIATE 174

2-[(1R,3S)-3 ,7-dichloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)benzenesulfonamide

To a solution of Intermediate 173 (130 mg, 0.30 mmol) in THF (3 mL),DMAP (4 mg, 0.033 mmol) and N,N-di-isopropylethylamine (0.04 mL, 0.39mmol) were added. The mixture was stirred at 0° C. beforemethanesulfonyl chloride (47 μL, 0.61 mmol) was added. The reactionmixture was stirred for 1 hour 30 minutes. Sodium hydride (18 mg, 0.45mmol) was added at 0° C. and stirred for 1 hour before the mixture washeated to reflux overnight. The reaction was quenched by the addition ofwater and extracted with EtOAc (x3). The combined organic phases weredried over sodium sulphate, filtered and concentrated in vacuo.Purification by column chromatography over silica gel using hexane/ethylacetate (0 to 100%) as eluent, the title compound was obtained as amixture of diasterisomers which were separated by Achiral SFCpurification, yielding 14 mg (11% yield) of the title compound as awhite solid. LCMS Method 3: RT 1.63 min, [M−H]⁺=448/450.

INTERMEDIATE 175

(7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,2,5]benzothiadiazoeine 5,5-dioxide

To a solution of Intermediate 174 (14 mg, 0.031 mmol) inN,N-dimethylformamide (0.6 mL) was added sodium hydride (60 mass %, 1.87mg, 0.047 mmol) and the reaction mixture was heated at 80° C. for 1hour. Water and EtOAc were added and the two phase were separated. Theaqueous layer was extracted with EtOAc and the combined organic layerswere washed with brine and filtered through a phase separator. Thesolvent was evaporated, yielding 10 mg (78% yield) of the title compoundas a green solid. LCMS Method 3: RT 1.70 min, [M−H]⁺=412/414

INTERMEDIATE 176

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-N-pyrimidin-2-yl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

To a solution of Intermediate 40 (600 mg, 1.40 mmol) and2-bromopyrimidine (334 mg, 2.10 mmol) in N,N-dimethylformamide (2.8 mL)was added N,N-di-isopropylethylamine. The reaction mixture was heated at80° C. for 4 hours and then at 110° C. overnight. Water and EtOAc wereadded and the reaction mixture was extracted with further ethyl acetate.The combined organic layer was filtered through a phase separator andthe solvent evaporated. The crude material was purified by columnchromatography over silica gel using hexane/ethyl acetate (0 to 100%)then DCM:MeOH (0 to 20%) as eluent, yielding 205 mg (29% yield) of thetitle compound as a pale yellow solid. LCMS Method 3: RT 2.24 min,[M−H]⁺=506/508.

INTERMEDIATE 177

Ethyl-N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]carbamate

To a solution of Intermediate 40 (400 mg, 0.93 mmol,) in dichloromethane(4.6 mL). N,N-diisopropylethylamine (0.24 mL, 1.4 mmol) followed byethyl chloroformate (116 μL, 1.21 mmol) were added and the reactionmixture was stirred for 1 hour. The solvent was evaporated and theresidue was purified by column chromatography (SiO₂, 0-100% EtOAc inhexane) to give the title compound (350 mg, 75% yield) as a pale yellowsolid. LCMS (ES+) Method 3: 500/502 (M+H)⁺, RT 2.23 minutes.

INTERMEDIATE 178

N-[1-(5-bromo-2-pyridyl)cyclobutyl]-2-methyl-propane-2-sulfinamide

2,5-dibromopyridine (1.4 g, 5.8 mmol) was dissolved in toluene (15 mL)and the reaction mixture was cooled to −60° C. after which timen-butyllithium (4 mL, 6.4 mmol) was added dropwise and the mixture wasstirred at this temperature for 10 minutes.N-cyclobutylidene-2-methyl-propane-2-sulfinamide (1 g, 5.77 mmol) in 1mL of toluene was added to the reaction mixture and stirred at −60° C.for 15 minutes. A saturated solution of NH₄Cl aq. was added and thereaction mixture was extracted with EtOAc and the combined organiclayers was washed with brine and filtered through a phase separator andthe solvent was evaporated under reduced pressure. The residue waspurified by column chromatography (SiO₂, 0-100% EtOAc in hexane) to givethe title compound (1.25 g, 65% yield) as a colourless oil. ¹H NMR (300MHz, Chloroform-d) δ 8.64 (dd, J=2.4, 0.7 Hz, 1H), 7.83 (dd, J=8.4, 2.4Hz, 1H), 7.42 (dd, J=8.5, 0.7 Hz, 1H), 4.31 (s, 1H), 2.72-2.57 (m, 3H),2.63-2.44 (m, 1H), 2.10 (ddt, J=18.7, 9.0, 7.0 Hz, 1H), 1.96-1.75 (m,1H), 1.22 (s, 9H).

INTERMEDIATE 179

N-[3-(5-bromo-2-pyridyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide

2,5-dibromopyridine (500 mg, 2.07 mmol) was dissolved in toluene (5 mL)and the reaction mixture was cooled to −60° C. before n-butyllithium(1.4 mL, 2.2 mmol) was added dropwise and the mixture stirred for 10minutes. 2-methyl-N-(oxetan-3-ylidine)propane-2-sulfinamide (420 mg, 2.2mmol) in 0.5 mL of toluene was added and the reaction mixture stirred at−60° C. for 15 minutes. A saturated solution of aqueous NH₄Cl was addedand the reaction mixture extracted with EtOAc and the combined organiclayers washed with brine, filtered through a phase separator and thesolvent evaporated under reduced pressure. The residue was purified bycolumn chromatography (SiO₂, 0-100% EtOAc in hexane) to give the titlecompound (550 mg, 80% yield) as a colourless oil. LC/MS: RT 1.35 mins(pH 10), [M+H]+=333/335. 1H NMR (400 MHz, Chloroform-d) δ 8.63 (dd,J=2.4, 0.7 Hz, 1H), 7.93 (dd, J=8.5, 2.3 Hz, 1H), 7.71 (dd, J=8.5, 0.8Hz, 1H), 5.41 (s, 1H), 5.33 (d, J=7.0 Hz, 1H), 5.05 (d, J=6.6 Hz, 1H),4.94 (d, J=6.6 Hz, 1H), 4.84 (dd, J=7.0, 0.8 Hz, 1H), 1.28 (s, 9H).

INTERMEDIATE 180 5-(4-bromophenyl)-2,4-dimethyl-1H-imidazole

To a solution of 1-(4-bromophenyl)-2-nitropropene (750 mg, 3.09 mmol),acetamidine hydrochloride (313 mg, 3.31 mmol) and potassium carbonate(421 mg, 3.015 mmol) in ethanol (12 mL) was added indium (III) chloride(33 mg, 0.149 mmol) and the reaction mixture was stirred at 70° C.overnight. Ethanol was evaporated and the crude reaction mixture wasdiluted with water (2 mL), and extracted with DCM. The organic layer wasdried over anhydrous sodium sulphate, filtered and evaporated undervacuum to give a yellow solid. The residue was purified by columnchromatography (hexane/ethyl acetate) to afford the title compound (270mg, 35%) as a pale yellow solid. LC/MS Method 3: RT 1.62 minutes,[M+H]⁺=251/253.

INTERMEDIATE 181

1-[2-[(1R,3R)-7-chloro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)phenyl]ethanone

Intermediate 60 (1.50 g, 3.49 mmol) was dissolved in toluene (20 mL),and tributyl(1-ethoxyvinyl)tin (2.53 mL, 7.67 mmol) andbis(triphenylphosphine)palladium(II) dichloride (250 mg, 0.36 mmol) wereadded. The reaction mixture was degassed and purged with N₂ 3 timesbefore heating at 105° C. for 18 hours. The reaction mixture was dilutedwith saturated aqueous KF solution and extracted with EtOAc (x3). Thecombined organics were, dried (sodium sulphate) and concentrated invacuo. The crude compound was purified by column chromatography elutingwith 0-10% MeOH:DCM to give the enol ether intermediate. Theintermediate was dissolved in THF/1N HCl (1:1, 40 mL) and stirred atroom temperature for 1 hour before neutralisation with saturated sodiumbicarbonate solution and extraction with EtOAc (2×50 mL). The organicswere combined and concentrated in vacuo to give the desired methylketone (1.22 g, 3.10 mmol, 89%). LC/MS: ESI MFI⁺393, retention time 1.31minutes Method 3.

INTERMEDIATE 182

tert-butyl2-{4-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]phenyl}pyrrolidine-1-carboxylate

To a solution of Example 11 (500 mg, 1.33 mmol) and tert-butyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate(768 mg, 2.00 mmol) in 1,4-dioxane (10 mL) was added K₃PO₄ (566 mg, 2.67mmol), tricyclohexylphosphonium tetrafluoroborate (52 mg, 0.14 mmol) andtris(dibenzylideneacetone)dipalladium(0) (108 mg, 0.11 mmol) withseveral drops of water. The reaction mixture was degassed and flushedwith nitrogen and then heated at 120 degrees in a microwave for 6 hours.The cooled reaction was diluted with H₂O (50 mL) and extracted withEtOAc x 3. The combined organics were dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by column chromatography, firstlywith EtOAc in DCM (0 to 100%) and then with 0-10% MeOH/DCM gave thetitle compound (575 mg, 66%). LC/MS Method 3: RT 2.40 minutes, m/z 487.2(-BOC).

INTERMEDIATE 182(a)

tert-Butyl(2-{4-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]phenyl}propan-2-yl)carbamate

The title compound can be prepared from Intermediate 171 (0.35 g, 0.93mmol, leq) and (tert-butyl 2-(4-bromophenyl)propan-2-ylcarbamate (leq)in accordance with the Method described for Example 137. Purification byflash chromatography on silica gel (0 to 100% EtOAc in DCM followed by 0to 10% MeOH in DCM) afforded the title compound as a brown solid. LC/MSMethod 3: RT 2.32 minutes, m/z 575.2

INTERMEDIATE 183

(1R,3R)-1-[2-chloro-6-(difluoromethoxy)phenyl]-7-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

The title compound may be prepared from Intermediate 10 in accordancewith the Method described for Intermediate 40.

INTERMEDIATE 184

tert-butyl {(1R,3R)-1-[2-chloro-6-(difluoromethoxy)phenyl]-7-br omo-6-fluoro-2 ,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

The title compound may be prepared from Intermediate 183 in accordancewith the Method described for Intermediate 42.

INTERMEDIATE 185

tert-butylN-[(1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]-N-(trideuteriomethyl)carbamate

Intermediate 184 (300 mg, 0.549 mmol) was dissolved in tetrahydrofuran(10 mL). Potassium bis(trimethylsilyl)amide (0.6 mL, 0.6 mmol) was addeddropwise at −78 degree and stirred for 30 minutes before the addition ofiodomethane-d3 (0.06 mL, 1 mmol). The reaction mixture was stirred at−78° C. for 10 minutes before being left in an ice-water bath for 2hours followed by 1 hour at room temperature. The reaction mixture wasquenched with saturated ammonium chloride solution and extracted withEtOAc, the organics dried over Na₂SO₄ and concentrated in vacuo.Purification by column chromatography, eluting with 0%-10% MeOH in DCM,to afford the title compound as an off white solid (320 mg, 99%). LC/MSMethod 3: RT 2.75 minutes, m/z 563.0/565.0

INTERMEDIATE 186

tert-butyl-N-[(1R,3R)-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]-N-trideuteriomethyl)carbamate

Intermediate 185 (310 mg, 0.49 mmol),[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]boronic acid (0.55 mmol, 1.1 eq),potassium carbonate (115 mg, 0.83 mmol), palladium(II) acetate (7 mg,0.03 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg,0.033 mmol) were dissolved in DMSO (5 mL, 70 mmol) and a drop of wateradded. The mixture was degassed thoroughly and nitrogen flushed. Themixture was heated for 1 hour in a microwave at 110° C. The mixture wasseparated between EtOAc and brine (25 mL of each) and the aqueousextracted with EtOAc (25 mL) and the combined organics washed with 3×20mL of brine, dried (phase separator)—and evaporated in vacuo.Purification by column chromatography on silica using a gradient EtOAcin DCM (0-100%) and then 1 to 15% MeOH in EtOAc to afford the titlecompound as an off white solid (210 mg, 64%). LC/MS Method 3: RT 2.28minutes, m/z 661.2.

INTERMEDIATE 187

2-[(1R,3R)-3-[tert-butoxycarbonyl(trideuteriomethyl)amino]-6-fluoro-7-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)benzoic acid

Into a 10 mL glass vial was placed Intermediate 186 (210 mg, 0.32 mmol),potassium carbonate (67 mg, 0.48 mmol), PdCl₂(dcypp) (15 mg, 0.025mmol), dimethyl sulfoxide (5 mL), water (0.1 mL, 6 mmol) and the vialequipped with a stirring bar was placed into a high pressure reactor.The headspace of the reactor was vacuum purge cycled with CO at 14 psi(x 3) and then left with a headspace pressure of 5 Bar. The vessel washeated to 105° C., (heating block temp) for a period of 24 hrs. Thereaction mixture was separated between ethyl acetate and water (20 mL ofeach) and the organic layer was extracted with a further 2×20 mL of 10%sodium carbonate solution. The combined aqueous layers were then treatedwith citric acid until no longer basic. The solution was then extractedwith ethyl acetate (3×20 mL) and these organics washed with 4×20 mL ofwater. The organics were dried (sodium sulfate), filtered and evaporatedin vacuo to afford the title compound as a white solid ˜90% pure. (120mg, 56%). LC/MS Method 3: RT 1.51 minutes, m/z 671.2

INTERMEDIATE 188

Ethyl2-[2-[(1R,3S)-7-chloro-3-methylsulfonyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)phenyl]sulfanylacetate

To a solution of Intermediate 161 (1.35 g, 2.88 mmol) in DCM (30 mL) at0° C. was added 4-dimethylaminopyridine (40 mg, 0.33 mmol),N,N-diisopropylethylamine (1.01 mL, 5.77 mmol) and methane sulfonylchloride (335 μL, 4.32 mmol) and stirred for 45 minutes. After this timethe reaction mixture was partitioned between DCM (40 mL) and water (50mL), layers separated and the aqueous phase extracted with DCM (3×50mL). Combined organics were washed with saturated aqueous sodiumbicarbonate solution (100 mL), dried (phase separator) and concentratedin vacuo to give the title compound as orange brown solid (1.57 g,quantitative yield). The crude product was progressed to the nextsynthetic step without further purification.

INTERMEDIATE 189 tert-Butyl N-[1-methyl-1-[5-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]ethyl]carbamate

Bis(pinacolato)diboron (4.55 g, 17.6 mmol), Intermediate 114 (3.70 g,11.7 mmol), potassium acetate (4.64 g, 46.8 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (1000 mg, 1.22 mmol) and 1,4-dioxane (35 mL)were placed in a RBF and then degassed. The mixture was then heated at105° C. for 1 hour, LCMS showed the completion of the reaction. Thereaction mixture was diluted with H₂O and extracted with EtOAc (x3), andthe organics combined, dried (MgSO₄), filtered and evaporated in vacuo.The crude material was used in the subsequent Suzuki coupling (3.6 g,80%). LC/MS Method 3: RT 1.04 minutes, m/z 378.

INTERMEDIATE 190

(7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6-(trideutero)methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 10 (650 mg, 1.65 mmol) was dissolved in tetrahydrofuran (15 mL,184 mmol) and potassium bis(trimethylsilyl)amide (1.8 mL, 1.8 mmol, 1mol/L in TNF) was added dropwise at −78° C. and stirred for 30 minutesbefore the addition of iodomethane-d³ (0.16 mL, 2.5 mmol). The reactionmixture was stirred at −78° C. for 10 minutes before being left in anice-water bath for 1 hour. The reaction mixture was quenched withaqueous saturated NH₄Cl solution and extracted with EtOAc (x3), thecombined organics were dried over Na₂SO₄, filtered and concentrated invacuo. The crude material was purified by column chromatography elutingwith 0%-10% MeOH/DCM to afford the title compound (570 mg, 84%). ¹H NMR(300 MHz, DMSO-d₆) δ 8.27 (dd, J=5.3, 4.1 Hz, 1H), 7.93-7.26 (m, 5H),6.24 (d, J=7.1 Hz, 1H), 5.23 (d, J=7.1 Hz, 1H), 3.49 (dt, J=14.3, 7.3Hz, 1H), 2.81 (d, J=13.8 Hz, 1H). LC/MS Method 3: RT 2.00 minutes, m/z411.0

INTERMEDIATE 191

tert-Butyl(2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-(trideutero)methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

Intermediate 190 (570 mg, 1.38 mmol), Intermediate 189 (1.8 g, 4.0mmol), potassium phosphate tribasic (1.05 g, 4.85 mmol) andtricyclohexylphosphonium tetrafluoroborate (65 mg, 0.17 mmol) wereplaced in a microwave vial and suspended in 1,4-dioxane (5 mL). Themixture was degassed and purged with N₂ 3 times, followed by theaddition of tris(dibenzylideneacetone) dipalladium(0) (130 mg, 0.13mmol) and three drops of water. The reaction mixture was heated at 140°C. for 2 hours in a microwave. The reaction cooled to room temperatureand quenched with H₂O (20 mL) and extracted with EtOAc (3×25 mL). Thecombined organics were dried over (Na₂SO₄), filtered and the solventsremoved in vacuo. The residue was purified by column chromatography onsilica eluting with 0 to 20% MeOH in EtOAc to afford the title compound(420 mg, 50%). LC/MS Method 3: RT 2.19 minutes, m/z 612.2

INTERMEDIATE 192

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl,di-O-benzyl phosphate.

Example 1 (26.0 g, 52.5 mmol) was suspended in dichloromethane (450 mL),placed under nitrogen and 5-methyl-1H-tetrazole (8.38 g, 99.7 mmol) wasadded and the mixture cooled to 5° C. in an ice bath, evacuated andrefilled with nitrogen twice then stirred for 5 minutes before addingdibenzyl N,N-di-isopropylphosphoramidite (28.2 mL, 83.9 mmol). Thereaction was stirred for 5 minutes before warming to room temperatureand stirred for one further hour. The mixture was cooled to 0° C. in anice bath then hydrogen peroxide solution (5.96 mL, 105 mmol, 50.0% w/win water) was added. The mixture was stirred for 1 hour and monitored byLCMS until oxidation was complete. The mixture was washed with 0.25Msodium metabisulphite solution (250 mL), then saturated aqueous sodiumbicarbonate solution (150 mL) and saturated brine (200 mL). The organicphase was dried (sodium sulfate), filtered and concentrated in vacuo toa pale yellow gum. The crude product was purified by chromatography onsilica (EtOAc to 15% MeOH in EtOAc) to give a crude residue which wasazeotroped with toluene (x3) to give the title compound as a whitesolid, (31.0 g, 78%). ¹H NMR (d⁶-DMSO , 300 MHz) δ: 1.87 (s, 6 H), 2.75(d, 1H, J=13.4 Hz), 3.50 (m, 1H), 4.92 (t, 1H, J=6.8 Hz), 5.02-5.05 (m,4H), 6.36 (d, 1H, J=7.1 Hz), 7.25 (m, 10H), 7.55 (m, 3H), 7.69 (d, 1H,J=11.5 Hz), 8.24 (dd, 1H, J=5.3, 4.2 Hz), 8.99 (s, 2H), 9.16 (d, 1H,J=6.8 Hz). LC/MS Method 3: RT 2.49 minutes, m/z 756.

INTERMEDIATE 193

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl,di-O-benzyl phosphate.

To a solution of Intermediate 192 (4.00 g, 5.29 mmol) in THF (70 mL) wasadded a solution of KHMDS in THF (1M, 5.60 mL, 5.60 mmol) dropwise at−78° C. and the mixture was stirred for 45 minutes before the additionof iodomethane (0.37 mL, 5.90 mmol). The reaction mixture was warmed to0° C. and stirred for 2.5 hours before the reaction completed. Thereaction mixture was quenched with saturated aqueous NH₄Cl solution andextracted with EtOAc (x3), the combined organics were dried with Na₂SO₄,filtered and concentrated in vacuo. Purification by columnchromatography eluting with 0-10% MeOH in EtOAc gave the title compound(3.20 g, 4.2 mmol, 79%). LC/MS Method 3: ES⁺(M+H)⁺770, retention time2.67 minutes.

INTERMEDIATE 194

(7R,14R)-11-chloro-1-(difluoromethoxy)-6-ethyl-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 148 (100 mg, 0.25 mmol) was dissolved in dry THF (2.5 mL).at the reaction was cooled to 0° C. and sodium hydride (60% in mineraloil) (12 mg, 0.30 mmol) was added. The reaction mixture was stirred atroom temperature for 35 minutes. Iodomethane (0.27 mL, 3.34 mmol) wasadded and the reaction mixture was stirred at 50° C. overnight. Thereaction mixture was quenched by addition of water (2 mL). The aqueouslayer was extracted by EtOAc (3×150 mL). The combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo. The residuewas purified over silica gel (heptane/AcOEt 1/1), yielding to 35 mg(32%) of the title compound as a white solid. LCMS (Method 3 ES+): RT2.60 min, [M+H]+418.

INTERMEDIATE 195 2-chloro-6-(trifluoromethoxy)benzaldehyde

N,N-Di-isopropylamine (38.4 ml, 271 mmo1) was added dropwise to asolution of n-butyllithium (1.6 M, 169 ml, 271 mmol) in THF (180 ml) at0° C. and the reaction mixture was stirred and allowed to warm to roomtemperature over 30 mins. The LDA solution was then added drop wise over10minutes to a solution of 1-chloro-3-(trifluoromethoxy)benzene (50 g,246 mmol) in THF (500 ml) at −70° C. and the resulting mixture wasstirred at −70° C. for 30 minutes. Finally N,N-dimethylformamide (23 ml,296 mmol) was added dropwise and the resultant mixture stirred at −70°C. for 30 minutes.

The reaction was quenched at −70° C. by addition of NH₄Cl (saturatedaqueous solution) to pH 7-8 and the resulting mixture was extracted withEtOAc (3×75 ml). The combined organic phases were washed with water (100ml), brine (100 ml), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to provide the title compound (55 g,99% yield).

LCMS (Method 16, ES+) RT 1.32 min., 224 [M+H]⁺.

INTERMEDIATE 196(S,E)-N-(2-chloro-6-(trifluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide

(S)-2-Methylpropane-2-sulfinamide (49.9 g, 411 mmol), potassium hydrogenphosphate (196 g, 1.12 mol) and potassium phosphate (238.2 g, 1.12 mol)were added to a solution of Intermediate 195 (84 g, 374 mmol) in THF(2000 ml) at room temperature. The resulting reaction mixture wasstirred at room temperature over 20 hours, filtered and the solid waswashed with EtOAc (3×200 ml). The filtrate was concentrated underreduced pressure to isolate the title compound (123 μ).

LCMS (Method 16, ES+) RT 1.45 min., 328 [M+H]⁺.

INTERMEDIATE 197 Ethyl(R)-3-4(S)-tert-butylsulfinyl)amino)-3-(2-chloro-6-(trifluoromethoxy)phenyl)-propanoate

A solution of ethyl bromoacetate (106.1 ml, 938.2 mmol) in THF (100 ml)was added dropwise over 2 hours to a solution of zinc (245.5 g, 3.75mol) and cuprous chloride (44.6 g, 450 mmol) in THF (800 ml) at 20-25°C. (NB: prior to this addition, the solution of Zn and CuCl was heatedat 70° C. over 30mins and cooled down to room temperature). Once theaddition was complete the reaction mixture was warmed to 50° C. over 1hour. The reaction mixture was cooled to 0° C. and a solution ofIntermediate 196 (123 g, 375.29 mmol) in THF (500 ml) was added dropwiseover 60mins. The resulting reaction mixture was warmed to roomtemperature over 20 hours and filtered over charcoal. The cake waswashed with EtOAc (3×250 ml) and the combined filtrates were washed withwater (500 ml), with 10% citric acid solution (1000 ml) and brine (500ml). The organic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give the title compound (155 g,99% yield).

LCMS (Method 16, ES+) RT 1.36 min., 416 [M+H]⁺.

INTERMEDIATE 198 Ethyl(R)-3-amino-3-(2-chloro-6-(trifluoromethoxy)phenyl)propanoatehydrochloride

4M Hydrochloric acid solution in 1,4-dioxane (326.1 ml, 1.3 mol) wasadded dropwise over 30 mins to a solution of Intermediate 197 (155 g,372.7 mmol) in a mixture of ethanol (107 ml) and diethyl ether (215 ml)at room temperature. The reaction mixture was then stirred for 2 hoursand the resulting suspension was filtered. The cake was washed with Et₂O(3×250 ml), with pentane (250 ml) and dried under suction to yield 49gof the title compound. The filtrate was concentrated under reducedpressure to provide a viscous residue. Et₂O was added to the residue,and the mixture was stirred over 20 hours. The resulting suspension wasfiltered and the isolated cake was washed with Et₂O (3×250 ml), withpentane (250 ml), and dried to yield 70 gof the title compound as thehydrochloride salt . LCMS (Method 16, ES+) RT 0.59 min., 311 [M+H]⁺.

INTERMEDIATE 199 Ethyl(R)-3-((5-bromo-4-fluoro-2-nitrophenyl)amino)-3-(2-chloro-6-(trifluoromethoxy)-phenyl)propanoate

1-Bromo-2,5-difluoro-4-nitrobenzene (30.2 g, 126.7 mmol) was added to asolution of ethyl Intermediate 198 (49 g, 140.8 mmol) inN,N-dimethylformamide (200 ml) and N,N-diisopropylamine (46.76 ml, 281.5mmol) was added. The reaction mixture was heated at 85° C. over twohours and, once cooled to room temperature, was then concentrated underreduced pressure. The resulting residue was dissolved in EtOAc (500 ml),washed with water (500 ml), 10% citric acid solution (2×500 ml) andbrine (500 ml). The organic phase was dried over magnesium sulfate,filtered and concentrated under reduced pressure. The resulting crudewas purified by SiO₂ flash chromatography with EtOAc/n-Heptane (2/98) aseluent to provide the title compound (45 g, 60% yield).

LCMS (Method 16, ES+) RT 1.60 min., 531 [M+H]⁺.

INTERMEDIATE 200(R)-3-((5-bromo-4-fluoro-2-nitrophenyl)amino)-3-(2-chloro-6-(trifluoromethoxy)phenyl)-propanal

Diisobutylaluminium hydride was added dropwise over 2 hours to asolution of Intermediate 199 (10 g, 18.9 mmol) in THF (100 ml) at −70°C. under argon. The reaction mixture was stirred over 2 hours at −70° C.The reaction was quenched at −70° C. by addition of NH₄Cl (saturatedaqueous solution) to pH=6 and the resulting suspension was filtered overa charcoal pad washing with EtOAc (75 mL). The filtrate was extractedwith EtOAc (3×75 mL. The combined organic phases were washed with water(100 ml), brine (100 ml), dried over MgSO₄, filtered and concentratedunder reduced pressure. The resulting residue was purified by SiO₂ flashchromatography with EtOAc/n-Heptane (1/4) as eluent to give the titlecompound (5.8 g, 63% yield).

LCMS (Method 17, ES+) RT 4.83 min., 487 [M+H]⁺.

INTERMEDIATE 201(R)-N-((R,Z)-3-((5-bromo-4-fluoro-2-nitrophenyl)amino)-3-(2-chloro-6-(trifluoromethoxy)-phenyl)propylidene)-2-methylpropane-2-sulfinamide

(R)-2-Methylpropane-2-sulfinamide (1.47 g, 11.9 mmol) was added to asolution of Intermediate 200 (5.8 g, 11.35 mmol) and titanium(IV)isopropoxide (3.36 ml, 11.35 mmol) in dichloromethane (100 ml) at roomtemperature. The reaction was heated at reflux for 20 hours.

After cooling to room temperature the reaction was quenched by additionof brine (50 ml) and the resulting mixture was stirred for 30 mins. Thesuspension was filtered over a charcoal pad, washed with dichloromethaneuntil the filtrate is colourless. The filtrate was washed with brine (20mL), dried over magnesium sulfate, filtered and concentrated underreduced pressure to afford the title compound (6.6 g, 99% yield).

LCMS (Method 18, ES+) RT 5.31 min., 588 [M+H]⁺.

INTERMEDIATE 202(R)-N-((1R,3R)-3-((5-bromo-4-fluoro-2-nitrophenyl)amino)-3-(2-chloro-6-(trifluoromethoxy)phenyl)-1-cyanopropyl)-2-methylpropane-2-sulfinamide

Scandium(III) trifluoromethanesulfonate (1.30 g, 2.62 mmol) was added toa solution of Intermediate 201 (7.7 g, 13.08 mmol) in dichloromethane(75 ml) at room temperature followed by trimethylsilyl cyanide (3.44 ml,26.16 mmol). The reaction mixture was then stirred over 92 hours at roomtemperature. The reaction was quenched by addition of water (100 ml) andthe resulting mixture was extracted with dichloromethane (2×50 ml).Combined organic phases were washed with brine (50 ml), dried overmagnesium sulfate, filtered and concentrated under reduced pressure toprovide the title compound (7.5 g, 93% yield).

LCMS (Method 18, ES+) RT 4.89 min., 615 [M+H]⁺.

INTERMEDIATE 203

7-Bromo-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-amine

Stannous chloride (11.78 g, 60.9 mmol) was added to a solution ofIntermediate 202 (7.5 g, 12.18 mmol) in ethanol (75 ml). The reactionmixture was heated at reflux over 2 hours and water (40 ml) was thenadded. The resulting solution was heated to reflux for 16 hours.

Once cooled to room temperature water (100 ml) and 2M Sodium hydroxideaqueous solution was added until pH=9.0 while keeping the solutiontemperature below 30° C. The resulting suspension was filtered over acharcoal pad and washed through with dichloromethane (5×50 ml). Thefiltrate was extracted with further dichloromethane (5×50 ml). Thecombined organic phases were washed with brine (20 ml), dried overmagnesium sulfate, filtered and concentrated under reduced pressure toprovide the title compound as cis/trans mixture of isomers (4/1, 3.00 g,53% yield).

LCMS (Method 18, ES+) RT 2.83 min., 464 [M+H]⁺.

INTERMEDIATE 204

tert-butyl((1R,3R)-7-bromo-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-yl)carbamate

Di-tert-butyl carbonate (1.99 ml, 9.04 mmol) was added to a solution ofIntermediate 203 (3.00 g, 6.46 mmol) in dichloromethane (20 ml) at roomtemperature. The reaction mixture was then stirred for 20 hours andconcentrated under reduced pressure. The resulting residue was purifiedby SiO₂ flash chromatography with EtOAc/n-Heptane (1/4) as eluent togive the title compound (1.8 g, 49% yield).

LCMS (Method 19, ES+) RT 2.51 min., 464 [M−BOC+H]⁺.

INTERMEDIATE 205

tert-Butyl ((1R,3R)-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-7-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H-benzo[c/]pyrrolo[1,2-a]imidazole-3-yl)carbamate

2-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propan-2-ol(0.26 g, 0.97 mmol) was added to a solution of Intermediate 204 (0.50 g,0.89 mmol) in 1,4-dioxane (5 ml) under argon. Potassium carbonate (0.370g, 2.66 mmol) was added to the solution and the reaction mixture waspurged with argon prior. bis(diphenylphosphino)ferrocenepalladium(II)dichloride dichloromethane complex (0.023 g, 0.026 mmol)was added and the reaction mixture was heated at 90° C. for 2 hours andthen cooled to room temperature. The reaction was quenched by additionof iced water and the resulting mixture was extracted with EtOAc (2×30ml). The combined organic phases were washed with brine (2×20 mL), driedover magnesium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by SiO₂ flashchromatography with DCM/MeOH (100/0 to 98/2) followed by SiO₂ flashchromatography with EtOAc/n-Heptane (3/7 to 1/1) as eluent to give thetitle compound (0.350 g, 64% yield).

LCMS (Method 20, ES+) RT 1.38 min., 622 [M+H]⁺.

INTERMEDIATE 206

2-(5-41R,3R)-3-amino-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-c]imidazole-7-yl)pyrimidin-2-yl)propan-2-ol

2N Hydrochloric acid solution in diethyl ether (2.8 ml, 5.63 mmo1) wasadded to a solution of Intermediate 205 (0.35 g, 0.56 mmol) indichloromethane (10 ml). The reaction mixture was stirred at roomtemperature over 72 hours.

Water was added and the aqueous phase was treated with 2N sodiumhydroxide aqueous solution until pH=12. The resulting mixture wasextracted with dichloromethane (2×50 ml) and then with EtOAc (2×50 ml).The combined organic phases were dried over magnesium sulfate, filteredand concentrated under reduced pressure to afford the title compound(300 mg).

LCMS (Method 20, ES+) RT 0.67 min., 522 [M+H]⁺.

INTERMEDIATE 207

tert-Butyl ((1R,3R)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-7-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)carbamate

2-(Azetidin-3-yl)propan-2-ol hydrochloride (0.208 g, 1.37 mmol) andcesium carbonate (0.890 g, 2.74 mmol) were added to a solution ofIntermediate 184 (0.500 g, 0.91 mmol) in a mixture of toluene/DMF (99/1,15 ml). The resulting mixture was purged with argon.(R/S)-(+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.018 g, 0.027mmol) and tris(benzylideneacetone)dipalladium(0) (0.009 g, 0.009 mmol)were added. The reaction mixture was then heated in a microwave at 100°C. over 2 hours. As traces of the expected azetidinyl derivative weredetected by LCMS, a second addition of all reagents[2-(azetidin-3-yl)propan-2-ol hydrochloride (0.208 g, 1.37 mmol), cesiumcarbonate (0.890 g, 2.74 mmol),(R/S)-(+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.018 g, 0.027mmol) and tris(benzylideneacetone)-dipalladium(0) (0.009 g, 0.009mmol)]was carried out. The reaction mixture was then heated in microwaveat 100° C. for a further 2 hours.

Water (50 ml) was added and the resulting mixture was extracted withEtOAc (3×50 ml). The combined organic phases were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by SiO₂ flash chromatography with DCM/MeOH (100/0to 95/5) as eluent to give the title compound (0.249 g, 47% yield).

LCMS (Method 20, ES+) RT 1.09 min., 581 [M+1-1]⁺.

INTERMEDIATE 208

2-(1-((1R,3R)-3-amino-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[c/]pyrrolo[1,2-a]imidazol-7-yl)azetidin-3-yl)propan-2-ol

Trifluoroacetic acid (0.33 ml, 4.29 mmol) was added to a solution ofIntermediate 207 (0.249 g, 0.428 mmol) in dichloromethane (5 ml). Thereaction mixture was stirred at room temperature over 24 hours.

Water (30 ml) was added and the aqueous phase was treated with 2N sodiumhydroxide aqueous solution until pH=12. The resulting mixture wasextracted with dichloromethane (2×30 ml) and EtOAc (1×30 ml). Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated under reduced pressure to provide the title compound (0.157g, 76% yield).

LCMS (Method 20, ES+) RT 0.64 min., 481 [M+H]⁺.

INTERMEDIATE 209

tert-butyl((1R,3R)-7-(4-(2-aminopropan-2-yl)phenyl)-1-(2-chloro-6-(trifluoromethoxy)-phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-yl)carbamate

A solution of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-aminein 1,4-dioxane (10 ml) was added to a solution of Intermediate 204(0.500 g, 0.885 mmol) in 1,4-dioxane (40 ml) under argon. Sodiumcarbonate (0.188 g, 1.77 mmol) and water (1 ml) were added to thesolution and purged with argon prior to addition oftris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.022 mmol) andtri-tert-butylphosphonium tretrafluoroborate (0.026 g, 0.088 mmol) wereadded and the reaction mixture was heated at 90° C. for 3 hours and thencooled to room temperature over 15 hours. Water (30 ml added and theresulting mixture extracted with EtOAc (2×30 ml). The combined organicphases were washed with brine (2×20 ml), dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by SiO₂ flash chromatography with DCM/MeOH (100/0 to 9/1)as eluent to give the title compound (0.250 g, 46% yield).

LCMS (Method 20, ES+) RT 0.91 min., 619 [M+H]⁺.

INTERMEDIATE 210

(1R,3R)-7-(4-(2-aminopropan-2-yl)phenyl)-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[c/]pyrrolo[1,2-a]imidazole-3-amine

2N Hydrochloric acid solution in diethyl ether (2.0 ml, 4.04 mmol) wasadded to a solution of Intermediate 209 (0.250 g, 0.404 mmol) indichloromethane (10 ml). The reaction mixture was stirred at roomtemperature for 72 hours. Water (30 ml) was added and the aqueous phasewas treated with 2N sodium hydroxide aqueous solution until to pH=12.The resulting mixture was extracted with dichloromethane (2×50 ml) andthen with EtOAc (2×50 ml). The combined organic phases were dried oversodium sulfate, filtered and concentrated under reduced pressure toafford the title compound (0.195 g, 93% yield).

LCMS (Method 20, ES+) RT 0.45 min., 519 [M+H]⁺.

INTERMEDIATE 211

tert-butyl((1R,3R)-7-(4-(2-aminopropan-2-yl)phenyl)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-yl)carbamate

The title compound was prepared from Intermediate 184 (0.500 g, 0.91mmol) in accordance with the synthetic procedure described forIntermediate 209 after purification by SiO₂ flash chromatography withDCM/MeOH (100/0 to 95/5) as eluent to give (0.324 g, 59% yield).

LCMS (Method 20, ES+) RT 0.86 min., 601 [M+H]⁺.

INTERMEDIATE 212

(1R,3R)-7-(4-(2-aminopropan-2-yl)phenyl)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-c]imidazole-3-amine

The title compound was prepared from Intermediate (0.324 g, 0.54 mmol)in accordance with the synthetic procedure described for Intermediate210 to afford the title compound (0.240 g, 89% yield).

LCMS (Method 20, ES+) RT 0.43 min., 501 [M+H]⁺.

INTERMEDIATE 213

N,N-diallyl-2-(5-bromopyrimidin-2-yl)propan-2-amine

To a mixture of 2-(5-bromopyrimidin-2-yl)propan-2-amine (3.00 g, 13.9mmol) and potassium carbonate (5.81 g, 41.6 mmol) in acetonitrile (50mL) was added allyl bromide (3.56 g, 29.1 mmol) and the mixture heatedto 50° C. for 4 hours. A further portion of allyl bromide (850 mg, 6.95mmol) was added and the reaction allowed to stir at room temperature for72 hours. The mixture was partitioned between diethyl ether (200 mL) and2M HCl. The organic phase was further extracted with 2M HCl (x2) and theaqueous phase washed with diethylether (x2). The aqueous phase wascooled on ice and made basic with solid sodium hydroxide. The aqueouswas then extracted with dichloromethane and the organic solvents driedover sodium sulphate, filtered and the volatiles removed in vacuo togive the title compound as a red oil, (3.40 g, 83% yield). LCMS Method 3(ES+) RT 2.63 minutes, 296/298 (M+H)+. ¹H NMR (300 MHz, DMSO-d⁶) 8.96(s, 2H), 5.80-5.60 (m, 2H), 5.10-4.85 (m, 4H), 3.20-3.10 (m, 4H), 1.50(s, 6H).

INTERMEDIATE 214

tert-butyl((1R,3R)-7-(2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)pyrimidin-5-yl)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)carbamate

A solution of2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine[prepared from5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)pyrimidine (0.500g, 1.45 mmo1), bis(pinacolato)diboron (0.450 g, 1.74 mmol) potassiumacetate (0.426 g, 4.34 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride dichloromethane complex (0.037 g, 0.043 mmol) in1,4-dioxane (10 ml) at 95° C. during 2 hours]in 1,4-dioxane (10 ml) wasadded to a solution of Intermediate 184 (0.650 g, 1.19 mmol) in1,4-dioxane (40 ml) under argon. Sodium carbonate (0.253 g, 2.38 mmol),water (1 ml) were added and the suspension purged with argon.tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.030 mmol) andtri-tert-butylphosphonium tretrafluoroborate (0.035 g, 0.119 mmol) wereadded and the reaction mixture was heated at 95° C. for 3 hours beforecooling to room temperature.

Water (30 ml) was added and the resulting mixture was extracted withEtOAc (2×30 ml). The combined organic phases were washed with brine (30ml), dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by

SiO₂ flash chromatography with DCM/MeOH (100/0 to 98/2) as eluent togive a brown viscous oil. Purification by preparative HPLC provided thetitle compound (0.310 g, 36% yield).

LCMS (Method 20, ES+) RT 1.98 min., 732 [M+H]⁺.

INTERMEDIATE 215

(1R,3R)-7-(2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)pyrimidin-5-yl)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine

2N Hydrochloric acid solution in diethyl ether (1.9 ml, 3.82 mmol) wasadded to a solution of Intermediate 214 (0.280 g, 0.382 mmol) indichloromethane (10 ml). The reaction mixture was stirred at roomtemperature for 3 hours.

Water (30 ml) was added and the aqueous phase was treated with 2N sodiumhydroxide aqueous solution until pH=12. The resulting mixture wasextracted with dichloromethane (2×30 ml) and with EtOAc (1×30 ml). Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated under reduced pressure to provide the title compound (0.200g, 78% yield).

LCMS (Method 16, ES+) RT 1.34 min., 632 [M+H]⁺.

INTERMEDIATE 216

(7R,14R)-11-(2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

A 0.6M solution of phenol in anhydrous DMSO (0.63 ml, 0.38 mmol) wasadded to a solution of Intermediate 215 (0.200 g, 0.32 mmol) inanhydrous DMSO (6 ml). Potassium carbonate (0.066 g, 0.47 mmol), dried4A molecular sieves (0.240 μ),dichloro-[bis(dicyclohexylphosphino)propane]palladium(II) (0.019 g,0.032 mmol) were added.

The reaction mixture was heated at 100° C. under 3 bars of carbonmonoxide over 24 hours.

EtOAc (100 ml) was added and the resulting mixture was washed with water(3×100 ml), brine (100 ml), dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The resulting crude residue waspurified by SiO₂ flash chromatography with DCM/MeOH (98/2 to 95/5) aseluent to afford the title compound (0.176 g, 89% yield) LCMS (Method20, ES+) RT 1.84 min., 624 [M+H]⁺.

Example 1(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 14 was dissolved with pTSA (2.092, 11.00 mmol, 5 eq) inmethanol (60 mL) and the mixture was stirred overnight at r.t. Thereaction mixture was diluted with EtOAC (200 mL) and a saturatedsolution of NaHCO₃ (200 mL) was added. The aqueous layer was extractedby 3×50 mL of EtOAc and the combined organic layers were dried overmagnesium sulfate, filtered and concentrated in vacuo. The obtainedresidue was taken up in a minimum of EtOAc, triturated, and filteredoff. The obtained precipitate was washed with EtOAc and dried to affordthe title compound (1.6 g, 76%).

¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 2H), 8.46 (d, J 8.0 Hz, 1H), 7.59 (m,2H), 7.48 (m, 2H), 7.38 (m, 1H), 6.84 (t, J 72.5 Hz, 1H), 6.37 (d, J 7.0Hz, 1H), 5.00 (t, J6.4 Hz, 1H), 4.68 (s, 1H), 3.51 (dt, J 13.4, 7.0 Hz,1H), 2.90 (d, J13.3 Hz, 1H), 1.67 (s, 6 H). LCMS Method 3 (ES⁺) RT 1.28min, 496.0 (M+H)+.

Example 2(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-methoxypropan-2-yl)pyrimidin-5-yl]-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 1 (8 mg, 0.01615 mmol) was dissolved in 0.2 mL of dry THF.Sodium hydride (60% in mineral oil, 1.6 mg, 0.04037 mmoL) was added andthe reaction mixture was heated at 65° C. for 1.5 h. Methyliodide (2.3mg, 0.01615 mmoL) was added at r.t. and the mixture stirred at r.t for16 h.

An excess of methyliodide was then added to the mixture and stirred for1 h.Water was added, the mixture was extracted with ethyl acetate, thecombined organic layers were dried over magnesium sulphate andconcentrated in vacuo to the title compound as an off white solid(3 mg,35.7%). ¹H NMR (400 MHz, DMSO) δ ppm 8.93 (s, 2H), 8.51 (d, J8.2 Hz,1H), 7.54 (m, 2H), 7.44 (t, J 8.2 Hz, 1H), 7.32 (d, J 8.1 Hz, 1H), 6.84(t, J 72.8 Hz, 1H), 6.28 (d, J 7.2 Hz, 1H), 4.98 (d, J 7.1 Hz, 1H), 3.52(s, 3H), 3.48 (m, 1H), 3.28 (s, 3H), 2.90 (d, J 13.6 Hz, 1H), 1.70 (s,6H). LCMS Method 3 (ES⁺) RT 1.39 min, 524.0 (M+H)⁺.

Example 3(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one

Intermediate 23 (525 mg, 0.8873 mmoL) was dissolved in 60 mL of methanoland cooled to 0° C. pTSA (1 g, 0.7031 mmoL) was added and the mixturestirred at room temperature for 16 h. The mixture was cooled down to 0°C., pTSA (1 g, 0.7031 mmoL) was added and the reaction mixture washeated at 60° C. for 2 h.The solvent was evaporated, the residue wastaken up in dichloromethane and washed with saturated aqueous sodiumhydrogen carbonate. The aqueous layer was extracted with DCM, thecombined layers were dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude compound was triturated with EtOAcfiltered, washed with a minimum of cold ethyl acetate and dried in vacuoto afford the title compound as a white solid (318 mg, 75%). ¹H NMR (400MHz, DMSO) 6 ppm 9.14 (d, J 6.9 Hz, 1H), 9.04 (s, 2H), 8.25 (dd, J 4.6Hz, J 4.1 Hz, 1H), 7.86-7.50 (m, 6H), 6.38 (d J 7.0 Hz, 1H), 5.12 (s,1H), 4.92 (t, J 6.8 Hz, 1H), 3.49 (m, 1H), 2.77 (d, J 13.3 Hz, 1H), 1.54(s, 6H). LCMS Method 3 (ES⁺) RT 1.26 min, 478.0 (M+H)⁺.

Example 4(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 24 was dissolved in methanol (20 mL/g), pTSA (0.600 g,3.152 mmol, 2.2 eq) was added and the reaction mixture was stirred atr.t. overnight. APTS (0.300 g, 1.176 mmol, 1.1 eq) was added and thereaction mixture was heated at 40° C. for 2 h, then 45° C. for 1 h andfollowing 50° C. for 15 minutes until disappearance of starting materialin LCMS. EtOAc (600 mL) was added and the mixture was washedsuccessively with a saturated solution of NaHCO₃ (200 mL) and asaturated solution of NaCl (200 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo, diluted with diethylether(150 mL) and concentrated in vacuo to afford the title compound as anoff-white solid (0.701 g, 99%).

¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 2H), 8.43 (d, J=8.2 Hz, 1H), 7.84 (d,J=8.5 Hz, 1H), 7.70 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.39 (t, J=8.2 Hz,1H), 7.26 (d, J=8.1 Hz, 1H), 6.79 (t, J=72.5 Hz, 1H), 6.33 (d, J=7.2 Hz,1H), 5.25 (d, J=7.1 Hz, 1H), 3.55 (d, J=7.1 Hz, 1H), 3.53 (s, 3H), 3.38(d, J=6.7 Hz, 1H), 2.89 (d, J=13.7 Hz, 1H), 1.57 (s, 6H). LCMS Method 3(ES⁺) RT 1.30 min, 492.0 (M+H)⁺.

Example 5(7R,14R)-1-(difluoromethoxy)-6-ethyl-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 25 (69 mg, 0.1113 mmoL) was dissolved in 1 mL of methanol,pTSA (105.9 mg, 34.0908 mmoL) was added and the mixture was stirred atr.t. for 16 h. EtOAc was added, washed with saturated aqueous sodiumhydrogen carbonate and brine. The organic layer was dried over magnesiumsulphate and concentrated in vacuo. The residue was purified bychromatography (SiO₂, 75% EtOAc in heptane)and triturated with diethylether to afford the title compound as an off white solid (23 mg, 40.9%).¹H NMR (400 MHz, CDCl₃) δ ppm 8.95 (s, 2H), 8.56 (d, J=7.4 Hz, 1H), 7.93(m, 1H), 7.81 (s, 1H), 7.54 (m, 1H), 7.48 (m, 1H), 7.35 (d, J=7.2 Hz,1H), 6.89 (t, J=72.3 Hz, 1H), 6.41 (s, 1H), 5.25 (m, 1H), 4.17 (m, 1H),3.95 (m, 1H), 3.59 (m, 1H), 2.93 (m, 1H), 1.68 (s, 6H), 1.49 (m, 3H).LCMS Method 3 (ES⁺) RT 1.36 min, 506.0 (M+H)⁺.

Example 6(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-(propan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 26 (10 mg, 0.0158 mmoL) was dissolved in MeOH (0.2 mL) andpTSA (6.6 mg, 0.0347 mmoL) was added. The mixture was stirred at r.t. .After 16 h, pTSA (6.6 mg, 0.0347 mmoL) was again added and the mixtureheated at 50° C. for 1 h. The reaction mixture was concentrated, theresidue dissolved in EtOAc washed with saturated aqueous sodium hydrogencarbonate and brine. The organic layer was dried over anhydrousmagnesium sulphate, concentrated in vacuo and triturated with diethylether to afford the title compound as a white solid (7 mg, 85.4% yield).

LCMS (ES⁺) Method 3 RT 1.42 min, 520.0 (M+H)⁺.

Example 7(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-5 (14H)-one

To a suspension of Intermediate 29 (50 mg, 0.0972 mmoL) in 1 mL oftoluene was added cyanomethylenetributylphosphorane (25.9 mg, 0.0282mmoL) and the reaction mixture was heated at 100° C. for 16 h. Themixture was cooled to r.t., taken up with EtOAc and washed with 1Nsodium hydroxide. The organic layer was dried over magnesium sulphateand concentrated in vacuo and triturated with diethyl ether to affordthe title compound as an off-white solid (3 mg, 6.2% yield).

¹H NMR (400 MHz, DMSO) δ ppm 8.96 (s, 2H), 8.08 (d, J=7.9 Hz, 1H), 7.76(d, J=11.3 Hz, 1H), 7.65 (t, J=73.8 Hz, 1H), 7.61 (m, 2H), 7.55 (m, 1H),6.47 (d, J=6.8 Hz, 1H), 6.10 (d, J=5.3 Hz, 1H), 5.17 (bs, 1H), 3.61 (m,1H), 3.18 (d, J=14.7 Hz, 1H), 1.49 (m, 6H). LCMS Method 3 (ES⁺) RT 1.36min, 497.0 (M+H)⁺.

Example 8(2Z)-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-5(14H)-ylidene]acetonitrileand(2E)-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-5(14H)-ylidene]acetonitrile

To a suspension of Intermediate 29 (50 mg, 0.0972 mmoL) in 1 mL oftoluene was added cyanomethylenetributylphosphorane (25.9 mg, 0.0282mmoL) and the reaction mixture was heated at 100° C. for 16 h. Thereaction was concentrated in vacuo and the residue was purified byreverse phase preparative LCMS (basic conditions). The residue wasdissolved in 2 mL of MeOH and passed through an acidic exchange-ioncolumn (400 mg, conditioning: MeOH 10 mL), followed by washing of thecolumn with 10 mL of methanol. The compound was discharged from theresin by elution of 10 mL of ammonia (1 M in methanol) and concentratedin vacuo. The residue was purified by preparative TLC with EtOAc—hexane(8/2), to afford the title compound as a colourless oil (2.5 mg, 4.95%yield) in a 6/4 mixture of Z/E isomers. ¹H NMR (400 MHz, CDCl₃) δ ppm8.93 (s, 1.2H), 8.90 (s, 0.8H), 7.69 (t, J=11.5 Hz, 1 H), 7.60 (d, J=7.6Hz, 0.6H), 7.40 (m, 3H), 7.25 (d, J=7.4 Hz, 0.4H), 6.84 (t, J=72.5 Hz,0.4H), 6.83 (t, J=72.3 Hz, 0.6H), 6.28 (m, 1H), 6.01 (d, J=4.3 Hz,0.4H), 5.87 (d, J=4.1 Hz, 0.6H), 5.34 (s, 0.6H), 5.07 (s, 0.4H), 3.32(m, 1H), 3.07 (d, J=14.1 Hz, 0.4 H), 3.02 (d, J=13.9 Hz, 0.6H)-1.67 (s,6H).

LCMS Method 3 (ES⁺) RT 1.39 min, 520.0 (M+H)⁺.

Example 9 (7R, 1 4R) and (7S, 14S)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7, 1 4-dihydro-7, 14-methanopyrido[1′,2′: 1 ,2]imidazo[4,5-d][2]b enzazocin-5 (6H)-one

The title compound was prepared from Intermediate 37 (300 mg, 0.71mmol), Na₂CO₃ (378 mg, 3.57 mmol) and dichloro[bis(dicyclohexylphosphino)propane]palladium(II) [Pd-133 from JohnsonMatthey](40 mg, 0.06 mmol), 1,4-dioxane (9 mL) under CO gas (5 bars) at150° C. for 15 h, following the protocol described for Intermediate 14(5.5 mg, 2%). ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 2H), 8.90 (s, 1H),8.70 (d, J 6.3 Hz, 1H), 8.28 (d, J 8.0 Hz, 1H), 7.95 (d, J 7.5 Hz, 1H),7.66 (d, J 9.4 Hz, 1H), 7.61 (d, J 9.4 Hz, 1H), 7.48 (t, J 7.4 Hz, 1H),7.27(t, J 7.7 Hz, 1H), 5.11 (s, 1H), 4.75 (d, J 6.1 Hz, 1H), 4.69 (t, J6.3 Hz, 1H), 2.44 (d, J 12.6 Hz, 2H), 1.54 (s, 6H). LCMS Method 3 (ES⁺)RT 1.64min, 412.0 (M+H)⁺.

Example 10

(7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

In a high pressure reactor, Intermediate 41 (927 mg, 2.076 mmol) wassolubilized in dry 1,4-dioxane (21 mL). Potassium carbonate (1.4 g, 10.4mmol) was added. A solution of palladium(II) acetate (23.3 mg, 0.1038mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (61.9 mg,0.1038 mmol) in 1 mL of dry dioxane was then added. The reactor wasclosed and degassed by 3 successive vacuum/nitrogen cycles and then withCO by 3 successive vaccuum/CO cycles. The bomb was charged with CO to 8psi and heated at 110° C. overnight. The reaction mixture wassubsequently filtered through a pad of celite and the pad rinsed by 50mL of EtOAc. The filtrate was concentrated in vacuo and the residuepurified over silica gel using AcOEt/MeOH 10/0 to 9/1 to yield 534 mg(65%) of the title compound as a pale brown solid. LCMS basic: RT 1.97min. (ES+) 394/396 (M+H)⁺. 1H NMR (400 MHz, DMSO): 9.13 (d, J=6.8 Hz,1H), 8.23 (dd, J1=6.9 Hz, J2 =2.6 Hz, 1H), 7.70 (d, J=10.1 Hz, 1H), 7.60(t, J=73.2 Hz, 1H), 7.51 (m, 3H), 6.30 (d, J=7.1 Hz, 1H), 4.88 (t, J=6.8Hz, 1H), 3.45 (m, 1H), 2.73 (d, J=13.4 Hz, 1H).

Example 11

(7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 40 (3.7 g, 8.6 mmol), activated molecular sieve 4A powder(1.2 μ), potassium carbonate (1.5 equiv., 13 mmol) followed bydichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II)(0.04 equiv., 0.35 mmol) were poured into the center of the 100 mL GlassParr reaction vessel. 3 cycles of vacuum (˜20 mmHg) followed by Argonwere applied to the closed reactor.

Anhydrous dimethyl sulfoxide (35 mL) was added, followed by phenol 5M inDMSO (1.1 equiv., 9.5 mmol). The solution was degassed by 3 vacuum (-20mmHg)/argon cycles followed by 3 cycles of vacuum/CO resulting in afinal CO pressure of 1 bar.

The mixture was stirred and heated overnight at 100° C. under the COatmosphere . The reaction was cooled to 30° C., the reactor vessel wasopened and EtOAc (40 mL) was added. The resulting mixture was filteredon a pad of Celite, evaporated in vacuo to yield a green oil.

The residue thus obtained was taken up in EtOAc (100 mL) and the organiclayer was washed with water, K₂CO₃ (saturated aqueous solution) andbrine (saturated aqueous solution). The aqueous layer was thenre-extracted with EtOAc (1×50 mL). The combined organic layers weredried over MgSO₄, filtered and evaporated to dryness. The obtained greensolid (3.65 g), was taken up in EtOAc, the insoluble material wasfiltered and rinsed with Et₂O to afford 1.06 g(33.1%) of the titlecompound as a grey solid.

The filtrate can be purified by flash chromatography to provideadditional product if required:

LCMS basic: MH+m/z=376, RT 1.90 minutes.

¹H NMR (300 MHz, DMSO) δ 9.12 (d, 1H, J=6.7 Hz), 8.23 (dd, 1H, J=7.0,2.4 Hz), 7.60 (m, 5H), 7.20 (dd, 1H, J=8.7, 2.1 Hz), 6.29 (d, 1H, J=7.1Hz), 4.87 (dd, 1H, J=6.7 Hz, 6.7 Hz), 3.46 (m, 1H), 2.72 (d, 1H, J=13.4Hz).

Example 12

(7R,14R)-11-chloro-1-(difluoromethoxy)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

Intermediate 45 (0.0525 mmol) was solubilized in THF (0.5 mL) andethanol (0.5 mL). Polymer-supported cyanoborohydride (33 mg, 0.132 mmol,4 mmol/g) was added. The reaction mixture was subjected to an orbitalshaker for 2 hours. The reaction mixture was then filtered andevaporated under reduced pressure. The crude material was purified bypreparative reverse phase HPLC (basic condition) to afford 7 mg (37%) ofthe title compound. LCMS basic (ES+) RT 3.5 min., 362/364(M+H)+. LCMSacidic (ES+) RT 2.12 min., 362/364(M+H)+.

¹H NMR (400 MHz, CDCl₃) δ 7.69 (m, 1H), 7.20 (m, 3H), 7.13 (m, 1H), 6.99(m, 1H), 6.73 (m, 1H), 6.10 (m, 1H), 4.77 (m, 1H), 3.66 (m, 1H), 3.21(m, 1H), 3.01 (d, 1H, J=15.3 Hz), 2.94 (m, 1H), 2.50 (m, 1H).

Example 13

[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]aceticacid

Intermediate 46 (34 mg, 0.076 mmol), 2-(1-hydroxy-1-methtylethyl)pyrimidine-5-boronic acid pinacol ester (2.5 equiv., 0.190 mmol), K₃PO₄(2 equiv., 0.152 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.05equiv., 0.0038 mmol), and tricyclohexylphosphonium tetrafluoroborate(0.12 equiv., 0.0091 mmol) were dissolved in a degassed mixture of 1,4dioxane (0.9 mL) and water (0.1 mL). The reaction mixture was heatedovernight at 105° C.

The mixture was cooled to r.t; water was added and the mixture extractedwith EtOAc. The aqueous layer was brought to pH 2-3 with HCl 1N,extracted with EtOAc, dried over magnesium sulphate, filtered andconcentrated in vacuo. The crude product was purified by reverse phasechromatography to afford 3 mg (7.5%) of the title compound as a whitesolid at 90% purity. LCMS (ES+) 522/523 (M+H)⁺

Example 14

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine-5(14H)-thione

To a solution of Intermediate 47 5 (15 mg, 0.025 mmol) in MeOH (1 mL)was added p-toluenesulfonic acid monohydrate (23.5 mg, 0.124 mmol). Theslurry was stirred overnight at r.t. The reaction mixture was quenchedwith NaHCO₃ (10% aqueous solution) and extracted with EtOAc (3×5 mL).The organic layer was dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by preparative TLC (DCM/MeOH 9/1)followed by a second purification by flash chromatography on silica gel(DCM/MeOH 100/0 to 95/5) to afford 9 mg (74%) of the title compound.LCMS acidic (ES+) RT 2.29 min., 494(M+H)+.

Example 15

(7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

Example 10 (178 mg, 0.452 mmol) was solubilized in dry THF (5 mL). At 0°C., borane dimethyl sulfide complex (340 μL, 2M solution in THF, 0.68mmol) was added. The reaction mixture was allowed to warm to r.t. andstirred overnight. The reaction mixture was concentrated in vacuo, theresidue was taken up in MeOH, stirred and heated under reflux for 48hours. The reaction mixture was concentrated in vacuo and the residuewas purified by reverse phase preparative LCMS (basic condition) toafford 65 mg (38%) of the title compound. LCMS basic (ES+) RT 3.55 min.,380/382(M+H)+. LCMS acidic (ES+) RT 3.56 min., 380/382(M+H)+. ¹H NMR(400 MHz, CDCl₃) 6 ppm 7.52 (d, 1H, J=9.6 Hz), 7.23 (m, 2H), 7.12 (m,1H), 6.97 (d, 1H, J=7.4 Hz), 6.71 (m, 1H), 6.09 (d, 1H, J=7.6 Hz), 4.70(d, 2H, J=5.9 Hz), 3.64 (m, 1H), 3.21 (m, 1H), 2.98 (d, 1H, J=15.3 Hz),2.48 (d, 1H, J=12.6 Hz).

Example 16

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

Example 5 (47 mg, 0.1237 mmol),2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(82 mg, 0.3105 mmol), tricyclohexylphosphonium tetrafluoroborate (5.524mg, 0.01485 mmol), tris (dibenzylideneacetone)dipalladium(0) (5.6 mg,0.0061 mmol), and K₃PO₄ (52.5 mg, 0.248 mmol) were placed in a tube, andfilled with argon. Degassed 1,4 dioxane (1 mL) and water (100 μL) wereadded and the resulting slurry was stirred at 105° C. for 2 hours. Thereaction mixture was cooled to r.t. before addition of EtOAc (2 mL) andwater (2 mL). The aqueous layer extracted with EtOAc (2×2 mL). Thecombined organic layers were dried over magnesium sulphate, filtered andconcentrated in vacuo. The crude was purified by reverse phasepreparative LCMS (acidic condition) to afford the TFA salt of the titlecompound which was solubilized in EtOAc (2 mL) and washed with asaturated solution of NaHCO₃. The aqueous layer was extracted with EtOAc(2×2 mL). The combined organic layers were dried over magnesiumsulphate, filtered and concentrated in vacuo to afford 33 mg (55%) ofthe title compound as a white solid. LCMS basic (ES+) RT 3.69 min.,482(M+H)+.

LCMS acidic (ES+) RT 1.91 min., 482(M+H)+. ¹H NMR (400 MHz, CDCl₃) 6 ppm8.87 (m, 2H), 7.62 (m, 1H), 7.25 (s, 1H), 7.20 (m, 1H), 7.12 (m, 1H),6.99 (m, 1H), 6.72 (m, 1H), 6.17 (m, 1H), 4.78 (m, 1H), 4.66 (m, 1H),3.66 (m, 1H), 3.25 (m, 1H), 3.05 (m, 1H), 2.53 (m, 1H), 1.65 (s, 6H).

Example 17

(7R,14R)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-1-methoxy-6,7-dihydro-7,14-methanobenzimidazo[1,2-1)][2,5]benzodiazocin-5 (14H)-one

Intermediate 57 (145 mg, 0.31 mmol) was dissolved in anhydrous DMA (3mL) in a 25 mL pressure reactor and Na₂CO₃ (165 mg, 1.56 mmol) wasadded. The mixture was degassed with a stream of nitrogen for 10 minutesthen the pressure vessel was sealed and subjected to threevacuum/nitrogen flush cycles, before repeating the process with carbonmonoxide and charging the pressure to 3.0 bar. The mixture was stirredfor 5 minutes then heated to 150° C. and stirred at this temperatureovernight. The reactor was allowed to cool to r.t. . The reactionmixture was diluted with EtOAc (20 mL) and filtered through a pad ofcelite, washing with excess EtOAc (20 mL). The filtrate was washed withwater (15 mL), then brine (15 mL), dried (Na₂SO₄) and concentrated todryness under vacuum to yield 160 mg of a crude residue. Purification byreverse phase chromatography (eluting with 0-100% MeCN (+0.1% NH₄OH)/H₂O(+0.1% NH₄OH)) to yield 2.1 mg (1.5%) of the title compound as a beigesolid. LCMS Method 6 (ES+) RT 3.52 min., 460.2 (M+H)+. ¹H NMR (500 MHz,MeOH-d4) δ 8.95 (d, J=1.5 Hz, 2H), 8.04 (dd, J=8.0, 1.1 Hz, 1H), 7.64(d, J=6.8 Hz, 1H), 7.50 (d, J=11.2 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H),7.37-7.29 (m, 1H), 6.62 (d, J=7.1 Hz, 1H), 4.96 (d, J=6.7 Hz, 1H), 4.13(s, 3H), 3.51 (dt, J=13.5, 6.9 Hz, 1H), 2.80 (d, J=13.4 Hz, 1H), 1.65(s, 6H), 1.63-1.57 (m, 1H).

Example 18

(7R,14R)-1,10-difluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of Intermediate 58 (200 mg, 0.44 mmol) in 1,4-dioxane (5mL) was added sodium carbonate (232 mg, 2.19 mmol) dichloropalladium;dicyclohexyl(3-dicyclohexyl-phosphanylpropyl)-phosphane (53.8 mg, 0.0877mmol). The reaction mixture was stirred at 160° C. under 5 bar of COpressure overnight. The reaction mixture was filtered through a celitepad and rinsed with ethanol (10 mL). The filtrate was evaporated and thecrude was dissolved in DCM (10 mL) and treated with a saturated aqueoussolution of NH₄Cl (5 mL) The organic layer was concentrated in vacuo,and the residue purified on silica gel (DCM/iPrOH/aq NH₃ 90:9:1),yielding 32 mg (16%) of the title compound. LCMS acidic Method 4 (ES+)RT 2.06 min., 448.2 (M+H)⁺

Example 19

(6R,12R)-2-chloro-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

A mixture of Intermediate 40 (500 mg, 1.17 mmol), potassium carbonate(322 mg, 2.33 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69mg, 0.12 mmol) and palladium(II) acetate (26 mg, 0.12 mmol) in1,4-dioxane (16 mL) was de-gassed and stirred at 110° C. under nitrogenfor 15 hours. The reaction mixture was cooled to ambient temperature and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69 mg, 0.12 mmol) andpalladium(II) acetate (26 mg, 0.12 mmol) were added to the reactionmixture. The solvent was de-gassed and the mixture was stirred at 110°C. for 18 hours. The reaction mixture was cooled to ambient temperature,filtered through celite and the latter was washed with EtOAc. Thecombined filtrate and washings were evaporated to dryness using an oilpump to give an oil which was purified by flash chromatography on silicagel (25 to 100% EtOAc in hexanes) to afford the title compound (249 mg,0.71 mmol, 61% yield) as a brown solid. LC/MS Method 3: RT 2.29 mins (pH10), m/z 348 and 350.

¹H NMR: (CD₃OD, 300 MHz) δ: 2.48 (d, J=11.2 Hz, 1H), 2.99 (dt, J=11.2,4.5 Hz, 1H), 4.87 (m, 1H (overlap with the residual water), 5.93 (d,J=4.5 Hz, 1H), 6.40 (d, J=8.1 Hz, 2H), 6.96 (t, J=74 Hz, 1H), 7.00 (d,J=8.1 Hz, 1H), 7.17 (dd, J=8.6, 2.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H),7.53 (d, J=8.6 Hz, 1H).

Example 20

2-{5-[(6R,12R)-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

A mixture of2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(purchased from commercial sources) (110.5 mg, 0.42 mmol), Example 19(97 mg, 0.28 mmol), K₃ PO₄ (118.3 mg, 0.56 mmol), andtricyclohexylphosphonium tetrafluoroborate (15.9 mg, 0.042 mmol) wassolubilized in 1,4-dioxane (1.95 mL) and water (0.19 mL) and the mixturedegassed with nitrogen before addition oftris(dibenzylideneacetone)dipalladium(0) (18.4 mg, 0.019 mmol). Thereaction mixture was heated at 105° C. for 15 hours or until LCMS showedreaction to be complete. The reaction mixture was cooled to ambienttemperature and the crude mixture was extracted with EtOAc (3×10 mL).The combined organic phases were washed with saturated brine (2×10 mL),dried over sodium sulphate, filtered and concentrated in vacuo to givean oil which was purified by preparative HPLC (pH=10) to afford thetitle compound (23 mg, 0.051 mmol, 18% yield) as a white solid. LC/MSMethod 3: RT 2.09 mins (pH 10), m/z 450 .

¹H NMR: (DMSO-d₆, 300 MHz) δ: 1.54 (s, 6H), 2.38 (d, J=11.3 Hz, 1H),2.94 (dt, J=11.3, 4.3 Hz, 1H), 4.91 (t, J=3.5 Hz, 1H), 5.11 (bs, 1H),5.91 (d, J=4.3 Hz, 1H), 6.34 (t, J=8.3 Hz, 2H), 6.97 (t, J=8.3 Hz, 1H),7.15 (d, J=3.7 Hz, 1H), 7.38 Hz (dd, J=73, 1.7 Hz, 1H), 7.54 (dd, J=8.4,1.7 Hz, 1H), 7.68-7.72 (m, 2H), 9.06 (s, 2H).

Example 21

1-[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]ethanone

Example 19 (245 mg, 0.7044 mmol) was dissolved in pyridine (2 mL) andacetic anhydride (2 mL). The mixture was stirred at 110° C. for 15hours. The reaction mixture was cooled to ambient temperature andquenched with 2N NaOH aq. (2 mL). The crude mixture was extracted withEtOAc (2×10 mL). The organic phase was washed with saturated brine (10mL), the combined organic phases was dried with sodium sulphate,filtered and concentrated in vacuo to give an oil which was purified byflash chromatography on silica gel (0 to 100% EtOAc in hexanes) toafford the title compound (177 mg, 65% yield) as a yellow solid. LC/MSMethod 3: RT 2.08 mins (pH 10), m/z 390 and 392.

¹H NMR: (CD₃OD, 300 MHz) δ: 2.66 (d, J=11.9 Hz, 1H), 2.69 (s, 3H), 3.20(dt, J=11.9, 4.5 Hz, 1H), 5.99 (d, J=3.9 Hz, 1H), 6.10 (d, J=4.5 Hz,1H), 6.94 (d, J=8.3 Hz, 1H), 7.08 (t, J=73.4 Hz, 1H), 7.20-7.28 (m, 2H),7.53 (d, J=8.7 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H).

Example 22

1-[(6R,12R)-11-(difluoromethoxy)-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]ethanone

The title compound was prepared from 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)pyrimidin-2-yl]propan-2-ol (179.9 mg, 0.68 mmol),and Example 21 according to a method involving the same procedural stepsas those described for Example 20, to give, following purification bypreperative HPLC (pH=10), a white solid (13 mg, 0.026 mmol, 5.8% yield):LC/MS Method 3: RT 1.93 mins (pH 10), m/z 492 .

¹H NMR: (DMSO-d₆, 300 MHz) δ: 1.54 (s, 6H), 2.61 (d, J=12.4 Hz, 1H),2.69 (s, 3H), 3.20 (dt, J=12.1, 4.5 Hz, 1H), 5.75 (s, 1H), 6.00 (d,J=3.2 Hz, 1H), 6.08 (d, J=4.3 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 7.29 (t,J=8.5 Hz, 1H), 7.46 Hz (dd, J=72.1, 1.7 Hz, 1H), 7.61 (dd, J=8.5, 1.8Hz, 1H), 7.76-7.80 (m, 2H), 8.21 (d, J=8.5 Hz, 1H), 9.07 (s, 2H).

Example 23

(6R,12R)-2-chloro-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

To a round bottom flask were added Intermediate 59 (2.80 g, 5.52 mmol),palladium(II) acetate (248 mg, 1.11 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.38 g, 2.21 mmol)and potassium carbonate (1.93 g, 13.8 mmol). The mixture was sealed andpurged 3 times with nitrogen. Toluene (55 mL) was added to the reactionmixture and the vial was kept under nitrogen and stirred for 15 hours at110° C. Then, the reaction mixture was cooled to ambient temperature,filtered through celite and the latter was washed with EtOAc. Thecombined filtrate and washings were evaporated to dryness using an oilpump to give an oil which was purified by flash chromatography in silicagel (0 to 100% EtOAc in Hexane) to afford the title compound (1.87 g,4.39 mmol, 79.5% yield) as a brown solid. LC/MS Method 3: RT 2.15 mins(pH 10), m/z 426 and 428.

¹H NMR: (DMSO-d6, 300 MHz) δ: 2.64 (d, J=12.0 Hz, 1H), 3.05 (s, 3H),3.18 (dt, J=12.0, 4.2 Hz, 1H), 5.92 (d, J=3.6 Hz, 1H), 6.08 (d, J=4.2Hz, 1H), 6.94 (dd, J=8.3, 0.7 Hz, 1H), 7.22 (dd, J=8.7, 2.1 Hz, 1H),7.34 (t, J=8.5 Hz, 1H), 7.44 (t, J=73.2 Hz, 1H), 7.47 (d, J=1.8 Hz, 1H),7.57 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H).

Example 24

2-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol, and Example 23according to a method involving the same procedural steps as thosedescribed for Example 20 to give, following purification by flashchromatography on silica gel (0 to 100% EtOAc in hexane), a white solid(542 mg, 84% yield). LC/MS Method 3: RT 2.04 mins (pH 10), m/z 528.

¹H NMR: (DMSO-d₆, 300 MHz) δ: 1.55 (s, 6H), 2.68 (d, J=12.1 Hz, 1H),3.05 (s, 3H), 3.24 (dt, J=12.3, 4.5 Hz, 1H), 5.12 (s, 1H), 5.96 (d,J=3.6 Hz, 1H), 6.13 (d, J=4.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 7.34 (t,J=8.5 Hz, 1H), 7.50 Hz (dd, J=72.4, 1.5 Hz, 1H), 7.62-7.56 (m, 2H), 7.67(d, J=1.5 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 9.07 (s, 2H).

Example 25

(6R,12R)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzoxazepine

A mixture of Intermediate 60 (287 mg, 0.668 mmol), cesium carbonate (440mg, 1.33 mmol), 8-hydroxyquinoline (10 mg, 0.068 mmol), in toluene (0.7mL) was degassed followed by the addition of copper (I) iodide (6.5 mg,0.033 mmol). The reaction mixture was stirred at 100° C. for 15 hours.The reaction mixture was cooled to ambient temperature, filtered throughcelite and the latter was washed with CH₂Cl₂. The combined filtrate andwashings were evaporated to dryness using an oil pump to give an oilwhich was purified by flash chromatography on silica gel (0 to 75% EtOAcin Hexane) to afford the title compound (40 mg, 0.1147 mmol, 17.17%yield) as a red solid. LC/MS Method 3: RT 2.5lmins (pH 10), m/z 349 and351.

¹H NMR: (CD₃OD, 300 MHz) δ: 2.75 (d, J=12.4 Hz, 1H), 3.13 (ddd, J=12.4,4.4, 1.4 Hz, 1H), 5.83 (d, J=1.4 Hz, 1H), 6.01 (d, J=4.4 Hz, 1H), 6.63(dd, J=8.4 Hz, 1H), 6.70 (dd, J=8.3 Hz, 1H), 7.01 (t, J=73.4 Hz, 1H),7.15 (t, J=8.4 Hz, 1H), 7.21 (dd, J=8.6,1.9 Hz, 1H), 7.53 (d, J=1.6 Hz,1H), 7.58 (d, J=8.6 Hz, 1H).

Example 26

2-{5-[(6R,12R)-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzoxazepin-2-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol,and Example 25 according to a method involving the same procedural stepsas those described for Example 20 to give, following purification byflash chromatography on silica gel (0 to 100% EtOAc in Hexane) a whitesolid (4.5 mg, 12% yield). LC/MS Method 3: RT 2.02 mins (pH 10), m/z451.

¹H NMR: (DMSO-d₆, 300 MHz) δ: 1.48 (s, 6H), 2.68 (d, J=12.9 Hz, 1H),3.09 (ddd, J=12.9, 4.2, 1.5 Hz, 1H), 5.05 (s, 1H), 5.92 (d, J=1.5 Hz,1H), 5.92 (d, J=4.2 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 6.65 (d, J=8.5 Hz,1H), 7.12 (t, J=8.3 Hz, 1H), 7.35(dd, J=72.4,1.5 Hz, 1H), 7.55 (dd,J=8.6, 1.7 Hz, 1H), 7.74 (m, 2H), 9.01 (s, 2H).

Example 27

(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine-11-carbonitrile

To a mixture of Example 11 (100 mg, 0.266 mmol), zinc cyanide (35 mg,0.298 mmol) and tetrakis (triphenylphosphine) palladium (31 mg, 0.0266mmol) was added N, N-dimethyl-formamide (3 mL). The mixture was degassedfor 3 minutes before being heated in microwave at 180° C. for 20minutes. The reaction mixture was partitioned between EtOAc (30 mL) andwater (40 mL), and the organics were washed with saturated brine (20mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by preparative HPLC (reverse phase) to give thetitle compound (5.1 mg, 5.2% yield) as a white solid. LC/MS Method 3:ESI MI-1⁺367, retention time 1.69 minutes (pH 10).

¹H NMR: (DMSO-d₆, 400 MHz) δ 9.17 (d, J=6.8 Hz, 1H), 8.23 (dd, J=7.5,1.8 Hz, 1H), 7.79 (m, 2H), 7.7-7.4 (m, 4H), 6.38 (d, J=7.1 Hz, 1H), 4.94(t, J=6.8 Hz, 1H), 3.50 (m, 1H), 2.77 (d, J=13.5 Hz, 1H).

Example 28

(7R,14R)-1-(difluoromethoxy)-11-[4-(methylsulfonyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from 4-methylsulfonylphenyl-boronicacid, and Example 11 according to a method involving the same proceduralsteps as those described for Example 20, following purification by flashchromatography on a 100 g-SNAP Biotage silica cartridge eluting with0%-10% MeOH/EtOAc followed by prep HPLC (reverse phase, 30%-50%MeCN/H₂O, pH 10) to give (8.83 mg, 0.178 mmol, 48%) as a white solid.

LC/MS Method 3: ESI MH⁺496.0, retention time 1.82 minutes (pH 10).

¹H NMR: (DMSO-d₆, 300 MHz) δ 9.14 (d, J=6.6 Hz, 1H), 8.23 (dd, J=5.7,3.8 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.9-7.4 (m, 9H), 6.37 (d, J=7.1 Hz,1H), 4.89 (t, J=6.6 Hz, 1H), 3.49 (m, 1H), 3.27 (s, 3H), 2.75 (d, J=13.4Hz, 1H).

Example 29

(7R,14R)-1-(difluoromethoxy)-11-(6-methoxypyridin-3-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from 2-methoxy-5-pyridineboronic acidand Example 11, according to a method involving the same proceduralsteps as those described for Example 20, following purification by flashchromatography to give (29 mg, 24%) as a white solid.

LC/MS Method 3: ESI MH⁺449.0, retention time 2.07 minutes (pH 10).

¹H NMR: (DMSO-d6, 400 MHz) δ 9.13 (d, J=6.8 Hz, 1H), 8.42 (d, J=2.32 Hz,1H), 8.23 (dd, J=5.9, 3.4 Hz, 1H), 7.9-7.4 (m, 7H), 6.93 (d, J=8.6 Hz,1H), 6.35 (d, J=7.1 Hz, 1H), 4.88 (t, J=6.8 Hz, 1H), 3.91 (s, 3H), 3.48(m, 1H), 2.73 (d, J=13.3 Hz, 1H).

Example 30

(7R,14R)-1-(difluoromethoxy)-11-(6-oxo-1,6-dihydropyridin-3-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

A mixture of Example 29 (22.4 mg, 0.050 mmol) and pyridine hydrochloride(29.0 mg, 0.246 mmol) were heated at 160° C. for 5 minutes and allowedto cool to ambient temperature. The mixture was then diluted withDCM/MeOH, concentrated and purified by prep HPLC (reverse phase) toafford the desired product (22.0 mg, 0.051 mmol, 78%) as a white solid.

LC/MS Method 3: ESI MH⁺435.0, retention time 1.34 minutes (pH 10).

¹H NMR: (DMSO-d6, 300 MHz) δ 11.8 (br s, 1H), 9.11 (d, J=6.7 Hz, 1H),8.22 (m, 1H), 7.9-7.3 (m, 8H), 6.44 (d, J=9.5 Hz, 1H), 6.31 (d, J=7.1Hz, 1H), 4.86 (t, J=6.7 Hz, 1H), 3.46 (m, 1H), 2.72 (d, J=13.4 Hz, 1H).

Example 31

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

A degassed mixture of Example 10 (299 mg, 0.56 mmol),6-(2-(trimethylsilyloxy)propan-2-yl)pyridine-3-boronic acid pinacolester (295 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0)(26.0 mg, 0.03 mmol), potassium phosphate tribasic (296 mg, 1.40 mmol),and tricyclohexylphosphonium tetrafluoroborate (26.0 mg, 0.07 mmol) in1,4-dioxane (4.5 mL) and water (0.5 mL) was heated to 105° C. overnight.The reaction mixture was cooled to r.t., diluted with EtOAc (50 mL) andwashed with water (2×50 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo. The residues were dissolved in DCM(4 mL) and 4M HCl solution (1.5 mL) was added. The solution was stirredat r.t for 1 hour. Saturated aqueous sodium carbonate solution (50 mL)was added, and the aqueous layer separated. The organic layer was washedwith brine (50 mL), dried (Na₂SO₄), filtered and concentrated in vacuoto give a crude oil. The crude material was purified by columnchromatography, eluting with 0-100% EtOAc in DCM, followed by 0-10% MeOHin EtOAc to give the title compound as an off-white powder (105 mg, 38%yield).

¹H NMR (400 MHz, DMSO) δ 9.15 (d, 1H, J=6.8 Hz), 8.61 (s, 1H), 8.26-8.21(m, 1 H), 7.90 (dt, 1H, J=1.9, 8.2 Hz), 7.77 (d, 1H, J=8.2 Hz), 7.61 (t,1H, J=75 Hz), 7.61 (d, 1H, J=11.5 Hz), 7.52-7.50 (m, 3H), 6.34 (d, 1H,J=7.1 Hz), 5.27 (s, 1H), 4.91 (t, 1H, J=6.8 Hz), 3.52-3.45 (m, 1H), 2.75(d, 1H, J=13.4 Hz), 1.49 (s, 6H). LCMS Method 3 ESI MH+495.1

Example 32

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)-6-methyl-pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was synthesised from Example 11 (240 mg, 0.639 mmol),and Intermediate 61 (213.2 mg, 0.7664 mmol), according to a methodinvolving the same procedural steps as those described for Example 20 togive, after purification by flash column chromatography, an oil, whichwas subsequently freeze dried to provide a white solid (115 mg, 0.234mmol, 36%).

1H NMR (400 MHz, DMSO) δ 9.15 (d, 1H, 6.6 Hz), 8.61 (s, 1H), 8.23 (dd,1H, 4.8 Hz), 7.73 (d, 1H, 8.3 Hz), 7.56, (m, 1H),7.51 (m, 3H), 7.22 (dd,1H, J=8.3, 1.7 Hz), 6.34 (d, 1H, J=7.1 Hz), 5.07 (s, 1H), 4.91 (t, 1H,J=6.6 Hz), 3.50 (m, 1H), 2.76 (d, 1H, J=13.3 Hz), 2.46 (s, 3H), 1.54 (s,6H). HPLC-MS Method 3 (pH10): MH+m/z=492.2, RT 1.81 minutes; Method 4(pH3): MH+m/z=492.2, RT 1.80 minutes.

Example 33

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-6-methyl-pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was synthesised from Example 10 (300 mg, 0.762 mmol),and Intermediate 61 (254.3 mg, 0.9142 mmol), according to a methodinvolving the same procedural steps as those described for Example 20,to give, after purification by column chromatography, an oil, which wassubsequently freeze dried to give a white solid (125 mg, 0.245 mmol,32%).

1H NMR (400 MHz, DMSO) δ 9.15 (d, 1H, J=6.8 Hz), 8.62 (s, 1H), 8.22 (dd,1H, J=6.2, 3.2 Hz), 7.65 (d, 1H, J=10.8 Hz), 7.53 (d, 1H, 7.8 Hz), 7.52(d, 1H, 7.8 Hz,), 7.51 (t, 1H, 72 Hz) 7.39 (d, 1H, J=6.6 Hz), 6.33 (d,1H, 7.1 Hz), 5.08 (s, 1H), 4.87 (t, 1H, J=6.8 Hz), 3.50 (dt, 1H, 13.6,6.8 Hz), 2.75 (d, 1H, J=13.4 Hz), 2.33 (d, 3H, 1 Hz), 1.54 (s, 6H).HPLC-MS Method 3 (pH10): MH+m/z=510.2, RT 1.88 minutes; Method 4 (pH3):MH+m/z=510.2, RT 1.91 minutes.

Example 34

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 11 (140 mg, 0.373 mmol) and6-(2-(trimethylsilyloxy)propan-2-yl)pyridine-3-boronic acid pinacolester (171 mg, 0.484 mmol) were added to a small microwave tube andtris(dibenzylideneacetone)dipalladium(0) (17.6 mg, 0.0186 mmol) andtricyclohexylphosphonium tetrafluoroborate (17.0 mg, 0.0447 mmol) wereadded with dioxane (2 mL), followed by K₃PO₄ (158 mg, 0.745 mmol) inwater (1 mL). The mixture was degassed and heated to 105° C. for 18hours. The mixture was diluted with EtOAc (30 mL) and washed with water(10 mL). The organic was concentrated in vacuo, re-dissolved in DCM (10mL) and 4.0M HCl in dioxane (5 mL) added and the mixture was stirred atr.t. for 1 hour. The mixture was partitioned between DCM and sodiumcarbonate (20 mL). The organic phase was dried (Na₂SO₄), filtered andconcentrated in vacuo.

Purification by preparative HPLC gave the title compound (35 mg, 20%) asa white solid.

¹H NMR: (d6-DMSO , 300 MHz) δ:1.48 (s, 6H), 2.74 (d, 1H, J=13.3 Hz),3.49 (m, 1H), 4.88 (t, 1H, J=6.7 Hz), 5.24 (s, 1H), 6.35 (d, 1H, J=7.0Hz), 7.49-7.53 (m, 3H), 7.69-7.72 (m, 3H), 7.66 (t, 1H, J_(H-F)=73.2Hz), 7.97 (dd, 1H, J=5.6, 8.2 Hz), 8.21-8.24 (m, 1H), 8.73 (d, 1H, J=1.8Hz), 9.13 (d, 1H, 6.8 Hz). LC/MS Method 3: RT 1.76 mins (pH 10), m/z477.

Example 35

(7R,14R)-1-(difluoromethoxy)-11-[4-(S-methylsulfonimidoyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 11 (200 mg, 0.532 mmol) andimino-methyl-oxo-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-sulfane(210 mg, 0.745 mmol), tris(dibenzylideneacetone)-dipalladium(0) (25.1mg, 0.0266 mmol) and tricyclohexylphosphonium tetrafluoroborate (24.2mg, 0.0639 mmol) were added to a small microwave tube. 1,4-Dioxane (2mL) was added, followed by K₃PO₄ (226 mg, 1.06 mmol) in water (0.3 mL).The mixture was degassed, placed under nitrogen and heated to 105° C.for 18 hours. LCMS showed a poor conversion. Another identical portionof catalyst, ligand and the boronate as above were added along with moredioxane (0.5 mL) and water (0.2 mL) and the mixture heated to 110° C.for a further 18 hours. The mixture was partitioned between EtOAc andwater (50 mL each) The organic layer was dried over sodium sulphate,filtered and concentrated in vacuo. The material was subjected to columnchromatography (silica, 0 to 20% MeOH in DCM) and the product containingfractions were concentrated in vacuo to give a brown solid, which, afterfurther purification by prep HPLC provided the title compound (9.1 mg,3.5%) as a white solid. ¹H NMR: (d6-DMSO , 300 MHz) 6: 2.74 (d, 1H,J=13.3 Hz), 3.11 (d, 3H, J=0.8 Hz), 3.49-3.54 (m, 1H), 4.24 (s, 1H),4.89 (t, 1H, J=6.7 Hz), 6.36 (d, 1H, J=7.0 Hz), 7.49-7.56 (m, 3H), 7.67(dt, 1H, J_(H-F)=73.3, 1.0 Hz), 7.71-7.74 (m, 2H), 7.80-7.83 (m, 2H),7.98-8.01 (m, 2H), 8.21-8.24 (m, 1H), 9.14 (d, 1H, 6.7 Hz). LC/MS Method3: RT 1.54 mins (pH 10), m/z 495.

Example 36

(1R,11R)-18-(difluoromethoxy)-6-fluoro-5-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-3,9,12-triazapentacyclo[9.8.1 .0²,¹ ⁰ .0³,⁸.0¹ ⁴ ,¹ ⁹]icosa-2(10),4,6,8,14(19),15,17-heptaen-13-one hydrochloride

Intermediate 72 (260 mg, 0.52 mmol), Na₂CO₃ (274 mg, 2.59 mmol) and2,2-dichloro-1,1,3,3-tetracyclohexyl-1λ⁵,3λ⁵-diphospha-2-palladacyclohexane(28 mg, 0.04 mmol) were suspended in degassed anhydrousdimethylacetamide (6 mL) in a 25 mL pressure vessel. The vessel wassealed and degassed thoroughly under vacuum then placed under anatmosphere of nitrogen. This process was repeated then the vessel wasevacuated and charged with 3 bar CO gas. The mixture was heated to 140°C. overnight whereon the internal pressure reached 4.8 bar. On coolingto r.t., the mixture was diluted with DCM:MeOH (50 mL) and washed withwater (30 mL). The aqueous layer was back extracted with DCM:MeOH (2×30mL). The combined organic layer was filtered through Celite andconcentrated under reduced pressure to afford a beige solid.

Purification by column chromatography (KP-NH, Biotage isolera) elutingwith 0-100% MeOH in DCM followed by purification using achiral SFC (20%MeOH: 80% CO₂ with Phenomenex Synergi 4u Polar RP 25cm column at15ml/min) gave the free base 65 mg (25%) as an off white solid.Suspension in 1:1 MeCN:water (3 mL) and treatment with 1N aqueous HCl(129.5 μL,leq) followed by freeze drying gave the title compound (67.5mg, 25%) as a fluffy colourless solid. Method 6 HPLC-MS: MH+m/z 496, RT2.27 min (100%), ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (s, 2H), 8.88 (d,J=6.1 Hz, 1H), 8.27 (d, J=7.1 Hz, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.78-7.68(m, 1H), 7.67-7.38 (m, 1H), 7.46-7.32 (m, 2H), 5.19 (d, J=6.4 Hz, 1H),4.73 (t, J=6.4 Hz, 1H), 3.77-3.15 (m, 2H), 2.43 (d, J=13.0 Hz, 1H), 1.54(s, 6H).

Example 37

(7R,14R)-1-(difluoromethoxy)-11-[2-(cis-1,3-dihydroxy-3-methylcyclobutyl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 79 (500 mg, 1.34 mmol), bis(pinacolato)diboron (408.0 mg,1.61 mmol), tricyclohexylphosphonium tetrafluoroborate (61.00 mg, 0.161mmol), potassium carbonate (22 mg, 0.161 mmol), potassium acetate (398mg, 4.02 mmol) were placed in a 8 mL vial filled with nitrogen.1,4-dioxane (4.8 mL) was added and the solution homogenized for 5minutes before addition of tris(dibenzylideneacetone)dipalladium(0) (63mg, 0.067 mmol). The reaction mixture was heated at 100° C., using apreheated oil bath, for 1 hour. The reaction mixture was filtered givinga clear crude solution of boronic acid used without further treatment.LCMS basic RT 0.920 min. (ES+) 339.0 (M+H)⁺ To Example 11 (127 mg, 0.338mmol), tricyclohexylphosphonium tetrafluoroborate (15.4 mg, 0.04055mmol), potassium phosphate (143 mg, 0.676 mmol) in a vial was added theabove described crude solution of3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]cyclobutanol,and water (0.12 mL).

The slurry was degassed before addition oftris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.0169 mmol). Theresulting solution was heated at 100° C. overnight. The reaction mixturewas filtered through sodium sulfate and rinsed with EtOAc (10 mL). Thefiltrate was evaporated, and the residue was purified over silica gel(100% EtOAc) yielding a slightly yellow glass (192 mg). LCMS basic (ES+)RT 2.35 min, 635.0 (M+H)⁺

The above intermediate (192 mg, 0.3029 mmol) was solubilised in THF (1.8mL) and tetrabutylammonium fluoride (1 M in THF) (0.9 mL, 0.9 mmol) wasadded drop-wise. The reaction mixture was stirred at r.t for 2 hours.The volatiles were removed in vacuo and the residue was partitionedbetween dichloromethane (20 mL) and water (20 mL). The DCM layer waswashed by 2×20 mL of water. The combined aqueous layers were extractedby 2×20 mL of DCM. The combined organic layers were washed by 4×20 mL ofwater and brine (1×10 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to give 109 mg of white solid. The white solid wasrecrystallized with 3 mL of isopropanol yielding 40 mg (26%) of thetitle compound as a white solid. LCMS basic Method 3 (ES+) RT 1.49 min,520.4 (M+H)⁺

Example 38

Ethyl[(6R,12R)-11-(difluoromethoxy)-3-fluoro-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]acetate

A solution of Intermediate 93 (250 mg, 0.39 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (36 mg, 0.058 mmol),cesium carbonate (261 mg, 0.80 mmol) and palladium acetate (12 mg, 0.053mmol) in toluene (8 mL) was degassed and heated to 110° C. for 15 hours.The reaction mixture was cooled to ambient temperature, partitionedbetween EtOAc (30 mL) and water (30 mL) and the phases were separated.The aqueous layer was extracted with EtOAc (3×10 mL). The combinedorganic phases were washed with saturated brine (10 mL), dried withsodium sulphate, filtered and concentrated in vacuo to give an oil whichwas purified by flash chromatography in silica gel (0 to 100% EtOAc inhexanes) to afford the title compound (169 mg, 78% yield) as a brownsolid.

LC/MS Method 3: RT 2.26 mins (pH 10), m/z 554.

¹H NMR: (CD3OD, 300 MHz) δ: 1.20 (t, J=7.1 Hz, 3H), 1.66 (s, 6H), 2.69(d, J=11.7 Hz, 1H), 3.01 (dt, J=11.7, 4.5 Hz, 1H), 4.44-4.15 (m, 4H),4.96 (d, J=3.4 Hz, 1H), 6.11 (d, J=4.5 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H),6.54 (d, J=8.3 Hz, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.05 Hz (t, J=73.8, 1.5Hz, 1H), 7.50 (d, J=11.2 Hz, 1H), 7.65 (d, J=6.7 Hz, 1H), 8.97 (d, J=1.6Hz, 2H).

Example 39(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound can be synthesised from Intermediate 158 and[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]boronic acid in accordancewith the Method described for Example 20.

¹H NMR: (DMSO-d6, 300 MHz) δ 8.95 (d, J=1.7 Hz, 1H), 8.23 (dd, J=6.7,2.8 Hz, 1H), 7.9-7.3 (m, 5H), 6.29 (d, J=7.1 Hz, 1H), 5.27 (d, J=7.1 Hz,1H), 5.15 (s, 1H), 3.52 (m, 1H), 3.36 (s, 3H), 2.84 (d, J=13.9 Hz, 1H),1.55 (s, 6H).

LC/MS: Method 3: MH⁺510.3, RT 2.04 minutes.

Preparative Example 40

1-[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]-2-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)ethanone

To a solution of Example 19 (50 mg, 0.14 mmol) in dichloromethane (1mL), was added triethylamine (24 uL, 0.17 mmol) followed by chloroacetylchloride (12 uL, 0.015 mL). After stirring for 1 hour, a further 0.11equiv of chloroacetyl chloride (1.2 uL, 0.014 mmol) was added and thereaction mixture was stirred for an additional 20 min. Triethylamine (24uL, 0.17 mmol) was added to the reaction mixture followed by3,7-dioxa-9-azabicyclo[3.3.1]nonane (11.5 mg, 0.168 mmol) and thereaction was stirred at room temperature for 18 h. The reaction mixturewas directly purified by column chromatography over silica gel usinghexane/ethyl acetate (0 to 100%) and then DCM/MeOH (from 0 to 20%) aseluent. A second purification by Prep-HPLC (basic conditions) afforded20 mg (27%) of the title compound. LCMS Method 3 (ES+) RT 2.91min.[M+H]⁺=517/519. ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (d, J=8.7 Hz, 1H),7.68-7.59 (m, 1H), 7.51-7.41 (m, 1H), 7.34-7.19 (m, 2H), 6.97 (d, J=8.3Hz, 1H), 6.25 (s, 1H), 6.07 (d, J=4.3 Hz, 1H), 4.14 (s, 3H), 4.06 (s,1H), 3.83 (s, 4H), 3.22 (d, J=12.1 Hz, 1H), 2.63 (d, J=12.1 Hz, 1H).

Example 41

tert-butyl(2-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-yl)carbamate

The title compound was prepared from tert-butylN-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]ethyl]carbamate,and Example 23 according to a method involving the same procedural stepsas those described for Example 20, to give, following purification byPrep-HPLC the title compound as a white solid (100.5 mg, 48% yield).LC/MS Method 3: RT 2.46 mins, [M+H]⁺=627. ¹H NMR (300 MHz, DMSO-d6) δ9.02 (s, 2H), 7.80 (d, J=8.5 Hz, 1H), 7.77-7.70 (m, 1H), 7.64-7.52 (m,2H), 7.50 (t,

J=73.5 Hz, 1H), 7.38 (d, J=73.0 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 6.93(d, J=8.2 Hz, 1H), 6.13 (d, J=4.3 Hz, 1H), 5.95 (d, J=4.0 Hz, 1H),3.29-3.16 (m, 1H), 3.07 (s, 3H), 2.68 (d, J=12.1 Hz, 1H), 1.60 (s, 6H),1.32 (bs, 9H).

Example 42

2-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-amine

To a solution of Example 41 (98 mg, 0.15 mmol) in 1,4-dioxane (2 mL) wasadded 4M HCl in dioxane (6 mL). The reaction was stirred for 1 hour atroom temperature and then the solvent was evaporated and the crude wasdissolved in dichloromethane (5 mL) and a saturated aqueous solution ofNa₂CO₃ was added until pH=8-9. The two phases were separated and theaqueous layer was extracted with dichloromethane (2×5 mL,) the combinedorganic layers were washed with brine, filtered through a phaseseparator and the solvent was evaporated. The solid obtained wastriturated in ether and filtered to give the title compound as a whitesolid (49.2 mg, 60% yield). LC/MS Method 3: RT 1.65 mins (pH 10),[M+H]⁺=527. ¹H NMR (300 MHz, DMSO-d₆) δ 9.04 (s, 2H), 7.85-7.71 (m, 2H),7.64-7.46 (m, 2H), 7.50 (t, J=73.4 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 6.93(d, J=8.3 Hz, 1H), 6.13 (d, J=4.3 Hz, 1H), 5.95 (d, J=3.9 Hz, 1H), 3.23(dt, J=12.2, 4.5 Hz, 1H), 3.07 (s, 3H), 2.68 (d, J=12.3 Hz, 1H), 2.31(bs, 2H), 1.47 (s, 6H).

Example 43

Azetidin-3-yl[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]methanone

To Intermediate 95 (158 mg, 0.24 mmol) in 1,4-dioxane (2 mL) was added4M HCl in 1,4-dioxane (2 mL) and the reaction was stirred for 10minutes. Methanol (2 mL) was added to keep the mixture in solution. Thereaction mixture was stirred for 3 hours before the solvent wasevaporated. The crude material was purified by preparative HPLC,yielding 22 mg (15%) of the title compound as a white solid. LCMS Method3: RT 1.57 min., [M-41]⁻¹=551. ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (d,J=1.7 Hz, 2H), 8.22 (d, J=8.6 Hz, 1H), 7.70 (d, J=11.5 Hz, 1H), 7.61 (d,J=6.9 Hz, 1H), 7.43 (t, J=73.8 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 6.92 (d,J=8.2 Hz, 1H), 6.07 (d, J=4.2 Hz, 1H), 5.61 (bs, 1H), 5.15 (bs, 1H),4.38 (bs, 1H), 4.07 (bs, 1H), 3.84 (bs, 4H), 3.20-3.08 (m, 1H), 2.64 (d,J=12.1 Hz, 1H), 1.56 (s, 6H).

Example 44

[(6R,12R)-11-(difluoromethoxy)-3-fluoro-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl][1-(methylsulfonyl)azetidin-3-yl]methanone

Methanesulfonyl chloride (3 μL, 0.038 mmol) was added to a solution ofExample 43 (17 mg, 0.03 mmol), N,N-diisopropylethylamine (6 μL, 0.034mmol) in DCM (0.3 mL) at 0° C. The reaction mixture was stirred at thistemperature for 10 minutes and then at room temperature for 3 hours. Thesolvent was evaporated and the crude material was purified bypreparative HPLC, yielding 1.5 mg (8%) of the title compound as a whitesolid. LCMS Method 3: RT 2.04 min., [M+H]⁺=629. ¹H NMR (300 MHz,Methanol-d4) δ 8.98 (d, J=1.6 Hz, 2H), 8.19 (s, 1H), 7.70 (d, J=6.6 Hz,1H), 7.55 (d, J=11.1 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 7.15 (t, J=73.5Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.21 (d, J=4.4 Hz, 1H), 5.80 (s, 1H),4.46 (dq, J=13.6, 6.2 Hz, 2H), 4.31 (td, J=13.6, 12.0, 5.9 Hz, 2H),3.30-3.18 (m, 1H), 3.04 (s, 3H), 2.73 (d, J=12.1 Hz, 1H), 1.66 (s, 6H).OH signal is exchanged with water. One proton is missing due tooverlapping with the solvent residual peak.

Example 45

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

A mixture of Intermediate 92 (500 mg, 0.9117 mmol), cesium carbonate(594 mg, 1.82 mmol), (+/−)-2,2″-bis(diphenylphosphino)-1,1′-binaphtyl(80 mg, 0.13 mmol) and palladium(II) acetate (25 mg, 0.11 mmol) intoluene (18 mL) was de-gassed and stirred at 110° C. under nitrogen for15 hours. The reaction mixture was cooled to ambient temperature,filtered through a pad of celite and washed with ethyl acetate. Thecombined filtrate and washings were evaporated to dryness using an oilpump to give an oil which was purified by flash chromatography on silicagel (25 to 100% EtOAc in hexanes) to afford the title compound (165 mg,0.35 mmol, 39% yield) as a brown solid. LC/MS Method 3: RT 1.99 mins,[M+H]⁺=468. ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (d, J=1.7 Hz, 2H), 7.61 (d,J=11.7 Hz, 1H), 7.53 (d, J=6.9 Hz, 1H), 7.21-7.13 (m, 1H), 7.17 (t,J=74.2 Hz, 1H), 6.98 (t, J=8.2 Hz, 1H), 6.35 (t, J=8.6 Hz, 1H), 5.90 (d,J=4.3 Hz, 1H), 5.14 (s, 1H), 4.92 (t, J=3.7 Hz, 1H), 2.95 (dt, J=9.0,4.3 Hz, 1H), 2.37 (d, J=11.4 Hz, 1H), 1.55 (s, 6H).

Example 46

Azetidin-3-yl[6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]methanone

HCl 4M in dioxane was added To Intermediate 97 (10 mg, 0.019 mmol) in1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxan (2 mL) and thereaction stirred for 5 hours before the solvent was evaporated. Thecrude material was purified by preparative HPLC, yielding 3 mg (39%) ofthe title compound as a white solid.

LCMS Method 3: RT 2.12 min, [M+H]⁺=431. ¹H NMR (300 MHz, DMSO-d6) δ 8.21(d, J=8.7 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.42(t, J=74.2 Hz, 1H), 7.27 (t, J=8.5 Hz, 1H), 7.20 (dd, J=8.7, 2.1 Hz,1H), 6.92 (d, J=8.1 Hz, 1H), 6.03 (d, J=4.3 Hz, 1H), 5.56 (d, J=3.9 Hz,1H), 4.41-4.30 (m, 1H), 4.10-3.65 (m, 4H), 3.09 (dt, J=12.1, 4.3 Hz,1H), 2.60 (d, J=12.0 Hz, 1H).

Example 47

cis-1-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}-3-methylcyclobutane-1,3-diol

A solution of tetrabutylammonium fluoride (1M in THF, 0.36 mL, 0.36mmol) was added to a solution of Intermediate 98 (82 mg, 0.12 mmol) intetrahydrofuran (0.72 mL) and the reaction was stirred at roomtemperature for 2 hours. The solvent was evaporated and the residue waspartitioned between dichloromethane (20 mL) and brine (20 mL). The twolayers were separated and the aqueous phase was extracted withdichloromethane (2×20 mL) and the combined organic layers were washedwith brine, filtered through a phase separator and the solvent wasremoved in vacuo. The crude material was purified by columnchromatography on silica gel with hexane/ethyl acetate (0 to 100%) aseluent, yielding 47 mg (68%) of the title compound as a brown solid.LCMS Method 3: RT 1.61 min. (pH 10), [M+H]⁺=570. ¹H NMR (300 MHz,DMSO-d₆) δ 9.09 (s, 2H), 7.81 (dd, J=8.5, 0.7 Hz, 1H), 7.78-7.76 (m,1H), 7.62 (dd, J=8.5, 1.8 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.50 (t,J=73,7 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.13 (d,J=4.4 Hz, 1H), 5.96 (d, J=3.8 Hz, 1H), 5.61 (s, 1H), 4.95 (s, 1H),3.32-3.18 (m, 1H), 3.07 (s, 3H), 2.97-2.85 (m, 2H), 3.05 (s, 3H), 2.68(d, J=12.1 Hz, 1H), 2.41 (d, 1.09 J=12.9 Hz, 2H).

Example 48

(6R,12R)-11-(difluoromethoxy)-2-{2-[(1s,5s)-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl]pyrimidin-5-yl}-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

The title compound was prepared from9-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-3,7-dioxa-9-azabicyclo[3.3.1]nonaneand Example 23 according to a method involving the same procedural stepsas those described for Example 20, to give, following purification bycolumn chromatography over silica gel using hexane/ethyl acetate (0 to100%) as eluent, the title compound as a white solid (114 mg, 58%yield).

LC/MS Method 3:: RT 1.88 mins (pH 10), [M+H]⁺=597. ¹ti NMR (300 MHz,DMSO-d6) δ 8.71 (s, 2H), 7.77-7.68 (m, 1H), 7.65-7.53 (m, 2H), 7.49 (t,J=1.6 Hz, 1H), 7.46 (t, J=73.5 Hz, 1H), 7.33 (t, J=8.5 Hz, 1H), 6.92 (d,J=8.3 Hz, 1H), 6.10 (d, J=4.3 Hz, 1H), 5.93 (d, J=3.9 Hz, 1H), 4.52 (s,2H), 4.10-3.93 (m, 4H), 3.77 (dd, J=11.1, 2.7 Hz, 4H), 3.21 (dt, J=12.3,4.4 Hz, 1H), 3.06 (s, 3H), 2.66 (d, J=12.1 Hz, 1H).

Example 49

[(6R,12R)-11-(difluoromethoxy)-3-fluoro-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]aceticacid

A solution of 1M sodium hydroxide in water (30 μL, 0.03 mmol) was addedto a solution of Example 38 (17 mg, 0.031 mmol) in ethanol (30 μL). Themixture was stirred for 3 hours and then purified directly bypreparative HPLC affording the title compound as a white solid (9 mg,54%). LC/MS Method 3: RT 1.68 minutes, [M+H]⁺=526. ¹H NMR (300 MHz,DMSO-d₆) δ 8.96 (d, J=1.7 Hz, 2H), 7.66-7.58 (m, 1H), 7.54 (d, J=6.9 Hz,1H), 7.35 (t, J=74.2 Hz, 1H), 7.04 (t, J=8.3 Hz, 1H), 6.37 (dd, J=8.3,4.7 Hz, 2H), 5.95 (d, J=4.3 Hz, 1H), 5.15 (s, 1H), 4.95 (d, J=3.4 Hz,1H), 3.86 (d, J=4.1 Hz, 2H), 2.95 (dt, J=11.3, 4.3 Hz, 1H), 1.55 (s,6H). COOH signal interchange with the water of the DMSO and one protonis missing due to overlapping with the residual signal of DMSO.

Example 50

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(pyridin-3-ylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

To Intermediate 99 (275 mg, 0.40 mmol), in a Schlenk tube were addedcesium acetate (383 mg, 1.99 mmol), cuprous iodide (155 mg, 0.79 mmol)and dimethylsulfoxide (0.4 mL) and the mixture was sealed and purged 3times with nitrogen. The reaction mixture was stirred at 100° C. for 18hours before water and ethyl acetate was added to the reaction mixtureand the two layers were separated. The aqueous layer was extracted withethyl acetate (x2) and the combined organic layers were filtered througha phase separator and the solvent evaporated. The crude material waspurified by column chromatography over silica gel using hexane/ethylacetate (0 to 100%) as eluent, yielding 8 mg (3%) of the title compoundas a white solid. LCMS Method 4: RT 2.15 min. (pH 3), [M+H]+=609. ¹H NMR(300 MHz, DMSO-d6) δ 9.24 (dd, J=2.5, 0.8 Hz, 1H), 8.95 (d, J=1.7 Hz,2H), 8.81 (dd, J=4.8, 1.5 Hz, 1H), 8.58 (ddd, J=8.2, 2.5, 1.6 Hz, 1H),7.75 (d, J=11.3 Hz, 1H), 7.64 (ddd, J=8.2, 4.8, 0.8 Hz, 1H), 7.56 (d,J=6.8 Hz, 1H), 7.42 (d, J=11.6 Hz, 1H), 7.41 (t, J=74.7 Hz, 1H), 7.27(t, J=8.5 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.36 (d, J=3.7 Hz, 1H), 6.08(d, J=4.3 Hz, 1H), 5.15 (s, 1H), 3.28-3.18 (m, 1H), 2.61 (d, J=12.3 Hz,1H), 1.55 (s, 6H).

Example 51

1-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}-3-(trifluoromethyl)azetidin-3-ol

The title compound was prepared from Example 23 (149 mg, 0.35 mmol), andIntermediate 100 (186 mg, 0.54 mmol), according to a method involvingthe same procedural steps as those described for Example 20. The crudematerial was purified by column chromatography (SiO₂, 40-100% EtOAc inhexane) and freeze dried from acetonitrile/water to give the titlecompound (119 mg, 56%) as a pale yellow solid. δ_(H) (300 MHz, DMSO-d₆)8.70 (s, 2H), 7.71-7.75 (m, 1H), 7.61 (d, 1H, J 1.3 Hz), 7.57 (d, 1H,J8.7 Hz), 7.49 (dd, 1H, J 73.9, 72.5 Hz), 7.46 (dd, 1H, J8.5, 1.7 Hz),7.42 (s, 1H), 7.33 (t, 1H, J 8.5 Hz), 6.92 (d, 1H, J 8.2 Hz), 6.10 (d,1H, J4.4 Hz), 5.93 (d, 1H, J3.5 Hz), 4.34 (m, 2H), 4.12 (d, 2H, J 9.9Hz), 3.17-3.25 (m, 1H), 3.06 (s, 3H), 2.63-2.70 (m, 1H). LCMS (ES+)Method 4: 609 (M+H)⁺, RT 2.21 minutes. LCMS (ES+) Method 5: 609 (M+H)⁺,RT 2.17 minutes.

Example 52

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from Intermediate 101 (192 mg, 0.31mmol), potassium carbonate (107 mg, 0.77 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (92 mg, 0.15 mmol),palladium(II) acetate (24 mg, 0.11 mmol) and toluene (3 mL) inaccordance with the Method described for Example 23. The crude materialwas purified by column chromatography (SiO₂, 20-100% EtOAc in hexane)and further purified by preparative HPLC to give the title compound (40mg, 24%) as a white solid. δ_(H) (300 MHz, DMSO-d₆) 8.97 (d, 2H, J 1.7Hz), 7.70-7.75 (m, 1H), 7.62 (d, 1H, J 6.8 Hz), 7.58 (d, 1H, J 8.6 Hz),7.46 (dd, 1H, J 74.1, 72.6 Hz), 7.35 (t, 1H, J 8.5 Hz), 6.94 (d, 1H, J8.1 Hz), 6.12 (d, 1H, J 4.3 Hz), 5.97 (d, 1H, J 3.6 Hz), 5.15 (s, 1H),3.19-3.28 (m, 1H), 3.09 (s, 3H), 2.68 (d, 1H, J 12.1 Hz), 1.56 (s, 6H).

LCMS (ES+) Method 5: 546 (M+H)⁺, RT 2.07 minutes.

LCMS (ES+) Method 4: 546 (M+H)⁺, RT 2.13 minutes.

Example 53

2-{5-[(6R,12R)-7-(cyclopropylsulfonyl)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from Intermediate 102 (110 mg, 0.17mmol), potassium carbonate (60 mg, 0.43 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,l′-binaphthyl (44 mg, 0.07 mmol),palladium(II) acetate (10 mg, 0.045 mmol) and toluene (2 mL) inaccordance with the synthetic Method of Example 23. The crude materialwas purified by by column chromatography (SiO₂, 20-100% EtOAc in hexane)and further purified by preparative HPLC to give the title compound (6mg, 6%) as an off-white solid. δ_(H) (300 MHz, DMSO-d₆) 8.98 (d, 2H, J1.7 Hz), 7.71 (d, 1H, J 11.4 Hz), 7.63 (s, 1H), 7.60 (d, 1H, J 2.1 Hz),7.47 (dd, 1H, J74.3, 72.3 Hz), 7.33 (t, 1H, J8.5 Hz), 6.92 (d, 1H, J8.1Hz), 6.11 (d, 1H, J 4.3 Hz), 5.98 (d, 1H, J3.5 Hz), 5.15 (s, 1H),3.16-3.25 (m, 1H), 2.85-2.95 (m, 1H), 2.63-2.70 (m, 1H), 1.56 (s, 6H),1.21-1.31 (m, 2H), 0.94-1.05 (m, 2H).

LCMS (ES+) Method 5: 572 (M+H)⁺, RT 2.71 minutes.

LCMS (ES+) Method 4: 572 (M+H)⁺, RT 2.22 minutes.

Example 54

2-{5-[(6R,12R)-7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from Intermediate 103 (125 mg, 0.18mmol), cesium carbonate (117 mg, 0.36 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,l′-binaphthyl (16 mg, 0.026 mmol)and palladium(II) acetate (6 mg, 0.027 mmol) and toluene (5 mL) by themethod of Example 38. The crude material was purified by columnchromatography (SiO₂, 20-50% EtOAc in hexane) and freeze dried fromacetonitrile/water to give the title compound (84 mg, 76%) as anoff-white solid.

δ_(H) (300 MHz, DMSO-d₆) 8.89 (d, 2H, J1.7 Hz), 7.55 (d, 1H, J 11.4 Hz),7.47 (d, 1H, J 6.9 Hz), 7.29 (dd, 1 H J 74.3, 73.0 Hz), 7.01 (t, 1H, J8.4 Hz), 6.54 (d, 1H, J 8.6 Hz), 6.36 (d, 1H, J 7.9 Hz), 5.88 (d, 1H, J4.4 Hz), 5.07 (s, 1H), 4.93 (d, 1H, J 3.3 Hz), 3.70-3.92 (m, 2H),3.33-3.52 (m, 2H), 2.90-2.98 (m, 1H), 2.31 (d, 1H, J 11.7 Hz), 1.48 (s,6H), 0.81 (s, 9H), 0.00 (s, 6H).

LCMS (ES+) Method 5: 626 (M+H)⁺, RT 3.37 minutes.

LCMS (ES+) Method 4: 626 (M+H)⁺, RT 3.41 minutes.

Example 55

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(2-hydroxyethyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

To a solution of Example 54 (78 mg) in THF (5 mL) was addedtetrabutylammonium fluoride (1M in THF, 0.26 mL, 0.26 mmol) and thereaction stirred at room temperature for 1 hour. After which time thereaction mixture was concentrated in vacuo and the residue waspartitioned between DCM (20 mL) and brine (20 mL), layers separated andorganics washed with brine (2×20 mL), the combined aqueous extractedwith DCM (2×20 mL). The combined organics were dried (phase separator)and the volatiles concentrated in vacuo. The crude material was purifiedby preparative HPLC to give the title compound (45 mg, 71%) as a whitesolid. 61-1(300 MHz, DMSO-d₆) 8.96 (d, 2H, J 1.7 Hz), 7.64 (d, 1H, J11.5 Hz), 7.55 (d, 1H, J 6.8 Hz), 7.36 (dd, 1H, J 74.5, 72.8 Hz), 7.08(t, 1H, J 7.6 Hz), 6.59 (d, 1H, J 8.5 Hz), 6.42 (d, 1H, J8.0 Hz), 5.95(d, 1H, J 4.4 Hz), 5.05-5.22 (m, 1H), 5.01 (d, 1H, J 3.2 Hz), 3.69-3.79(m, 1H), 3.54-3.65 (m, 1H), 3.36-3.53 (m, 2H), 3.12-3.21 (m, 1H),2.94-3.03 (m, 1H), 2.44 (d, 1H, J 11.3 Hz), 1.55 (s, 6H).

LCMS (ES+) Method 5: 512 (M+H)⁺, RT 1.91 minutes.

LCMS (ES+) Method 4: 512 (M+H)⁺, RT 1.91 minutes.

Example 56

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(phenylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from Intermediate 104 (174 mg, 0.25mmol), potassium carbonate (90 mg, 0.64 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,l′-binaphthyl (62 mg, 0.10 mmol),palladium(II) acetate (14 mg, 0.062 mmol) and toluene (3 mL) by themethod of Example 23. The crude material was purified by columnchromatography (SiO₂, 0-100% EtOAc in hexane) and further purified bypreparative HPLC to give the title compound (6 mg, 4%) as a white solid.

δ_(H) (300 MHz, DMSO-d₆) 8.96 (d, 2H, J 1.6 Hz), 8.10-8.16 (m, 2H), 7.77(d, 1H, J 11.3 Hz), 7.55-7.71 (m, 4H), 7.40 (dd, 1H, J74.3, 72.1 Hz),7.31-7.36 (m, 1H), 7.21 (t, 1H, J 8.4 Hz), 6.84 (d, 1H, J8.1 Hz), 6.34(d, 1H, J3.6 Hz), 6.07 (d, 1H, J 4.1 Hz), 5.03-5.27 (m, 1H), 3.17-3.27(m, 1H), 2.51-2.56 (m, 1H), 1.55 (s, 6H).

LCMS (ES+) Method 5: 608 (M+H)⁺, RT 2.45 minutes.

LCMS (ES+) Method 4: 608 (M+H)⁺, RT 2.48 minutes.

Example 57

2-(5-{(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-[(6-methoxypyridin-3-yl)sulfonyl]-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl}pyrimidin-2-yl)propan-2-ol

To a microwave vial was added Intermediate 105 (146 mg, 0.20 mmol),potassium carbonate (71 mg, 0.51 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (51 mg, 0.08 mmol),palladium(II) acetate (11 mg, 0.05 mmol) and toluene (2.5 mL). Thereaction mixture was sealed and degassed with nitrogen and heated to120° C. in a microwave for 2 hours. After which time the reaction wascooled to room temperature, filtered through celite and washed withEtOAc and DCM. The filtrate was concentrated in vacuo and the crudematerial purified by column chromatography (SiO₂, 0-100% EtOAc inhexane) and further purified by preparative HPLC to give the titlecompound (6 mg, 5%) as an off-white solid.

δ_(H) (300 MHz, DMSO-d₆) 8.95 (d, J 1.7 Hz, 2H), 8.88 (dd, J 2.7, 0.7Hz, 1H), 8.45 (dd, J 8.9, 2.7 Hz, 1H), 7.74 (d, J 11.3 Hz, 1H), 7.56 (d,J 6.8 Hz, 1H), 7.47 (d, J 8.6 Hz, 1H), 7.41 (dd, J 74.1, 72.2 Hz, 1H),7.28 (t, J 8.5 Hz, 1H), 7.00 (dd, J 8.9, 0.7 Hz, 1H), 6.87 (d, J 8.2 Hz,1H), 6.32 (d, J 3.8 Hz, 1H), 6.07 (d, J 4.3 Hz, 1H), 5.15 (s, 1H), 3.89(s, 3H), 3.23 (dt, J 12.3, 4.4 Hz, 1H), 2.57 (d, J 12.3 Hz, 1H), 1.55(s, 6H).

LCMS (ES+) Method 5 639 (M+H)⁺, RT 2.36 minutes.

LCMS (ES+) Method 4 639 (M+H)⁺, RT 2.48 minutes.

Example 58

[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-oxo-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]aceticacid

To a solution of Intermediate 106 (20.0 mg, 0.03 mmol) in THF (1 mL) wasadded a solution of tetrabutylammonium fluoride (0.4 mL, 0.4 mmol, 1M inTHF) at ambient temperature and the reaction stirred for 72 hours. Thereaction mixture was partitioned between water (10 mL) and DCM (2×10mL), and the organics were combined, dried with Na₂SO₄, filtered andconcentrated in vacuo. Purification by preparative HPLC afforded thetitle compound (3.0 mg, 19%).

¹H NMR (300 MHz, DMSO-d₆) δ 9.06 (s, 2H), 8.27 (dd, J=6.3, 3.2 Hz, 1H),7.84-7.56 (m, 3H), 7.55-7.40 (m, 2H), 6.82 (s, 1H), 6.31 (d, J=7.0 Hz,1H), 5.22 (d, J=7.2 Hz, 1H), 5.12 (s, 1H), 4.56 (d, J=16.3 Hz, 1H), 3.86(d, J=16.1 Hz, 1H), 3.56 (dt, J=14.0,7.2 Hz, 1H), 2.89 (d, J=13.8 Hz,1H), 1.55 (s, 6H). LC/MS Method 3: MFI⁺536, retention time 1.19 minutes.

Example 59

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-(2,2,2-trifluoroethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one

To a solution of Intermediate 107 (100.0 mg, 0.148 mmol) in THF (10 mL)were added HCl (20 mL, 40 mmol, 2M in 1,4 dioxan), and the mixture wasstirred at room temperature for 5 hours. The reaction mixture wasneutralised with NaOH (10% aqueous solution) and extracted with DCM(2×10 mL), the organics were combined, dried with Na₂SO₄, filtered andconcentrated in vacuo. Purification by preparative HPLC afforded thedesired product (15.0 mg, 18%).

¹H NMR (300 MHz, DMSO-d₆) δ 9.06 (s, 2H), 8.26 (dd, J=7.0, 2.5 Hz, 1H),8.03-7.37 (m, 6H), 6.38 (d, J=7.0 Hz, 1H), 5.45 (d, J=7.3 Hz, 1H), 5.12(s, 1H), 4.94-4.70 (m, 1H), 4.59 (dt, J=15.3, 9.3 Hz, 1H), 3.60 (dt,J=14.3, 7.3 Hz, 1H), 2.90 (d, J=13.9 Hz, 1H), 1.55 (s, 6H). LC/MS Method3: ESI MH⁺560, retention time 2.19 minutes.

Example 60

(7R,14R)-1-(difluoromethoxy)-6-(2-hydroxyethyl)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of Intermediate 109 (60.0 mg, 0.094 mmol) in THF (5.0 mL)were added aqueous HCl (10 mL, 20 mmol, 2M), and the mixture was stirredat room temperature for 18 hours before the completion of the reaction.The reaction mixture was neutralised with 10% aqueous NaOH solution andextracted with DCM (2×10 mL). The organics were combined, dried withNa₂SO₄, filtered and concentrated in vacuo. Purification by preparativeHPLC (reverse phase) afforded the title compound (27.0 mg, 55%). ¹H NMR(300 MHz, DMSO-d₆) δ 9.06 (s, 2H), 8.31 (dd, J=5.5, 4.1 Hz, 1H),7.99-7.39 (m, 6H), 6.32 (d, J=7.0 Hz, 1H), 5.38 (d, J=7.2 Hz, 1H),4.01-3.88 (m, 2H), 3.88-3.71 (m, 4H), 3.54 (dt, J=14.1, 7.2 Hz, 1H),2.85 (d, J=13.8 Hz, 1H), 1.55 (s, 6H). LC/MS Method 3: ESI MH⁺522,retention time 1.69 minutes.

Example 61

(7R,14R)-1-(difluoromethoxy)-6-(2-hydroxy-2-methylpropyl)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of Intermediate 23 (120 mg, 0.2 mmol) in DMF (4 mL) wereadded cesium carbonate (320 mg, 1.01 mmol) and1-iodo-2-methylpropan-2-ol (50.0 μL, 0.41 mmol), and the mixture washeated in a microwave at 150° C. for 22 hours. The reaction mixture waspartitioned between water and DCM (2×10 mL), and the organics werecombined, dried with Na₂SO₄, filtered and concentrated in vacuo.Purification by preparative HPLC (reverse phase) afforded the titlecompound (12.0 mg, 11%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.06 (s, 2H), 8.32(dd, J=5.5, 4.0 Hz, 1H), 7.99-7.37 (m, 6H), 6.34 (d, J=6.9 Hz, 1H), 5.65(d, J=7.5 Hz, 1H), 4.05 (d, J=13.7 Hz, 1H), 3.72 (d, J=13.7 Hz, 1H),3.58 (dd, J=14.0, 7.0 Hz, 1H), 2.86 (d, J=13.8 Hz, 1H), 1.55 (s, 6H),1.21 (d, J=5.7 Hz, 6H). LC/MS Method 3: ESI MH⁺ 550, retention time 1.57minutes.

Example 62

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-(trideutero)methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 111 (36.0 mg, 0.06 mmol) was dissolved in a solution of HClin dioxane (4 mL, 4 M) and stirred at room temperature for 1 hour. Thereaction mixture was concentrated in vacuo and purified on silicaeluting with 0-10% MeOH/DCM to give the title compound (10 mg, 34%). ¹HNMR (400 MHz, D₂O) δ 8.97 (s, 2H), 8.21 (dd, J=7.4, 2.0 Hz, 1H), 7.94(dd, J=1.7, 0.7 Hz, 1H), 7.74 (dd, J=8.7, 0.7 Hz, 1H), 7.59 (dd, J=8.7,1.7 Hz, 1H), 7.50-7.36 (m, 1H), 7.15 (d, J=2.4 Hz, 2H), 6.64 (d, J=7.1Hz, 1H), 5.51 (d, J=7.2 Hz, 1H), 3.59 (dt, J=14.4, 7.3 Hz, 1H), 3.03 (d,J=14.2 Hz, 1H), 1.75 (s, 6H). LC/MS Method 3: ESI MH⁺ 494, retentiontime 1.45 minutes.

Example 63

(7R,14R)-1-(difluoromethoxy)-11-{6-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyridin-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of Intermediate 138 (300 mg, 0.84 mmol) and Example 11(350 mg, 0.93 mmol) in 1,4-dioxane (5 mL) and water (0.4 mL) were addedK₃PO₄ (540 mg, 2.55 mmol), tricyclohexylphosphonium tetrafluoroborate(38 mg, 0.1 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (40 mg,0.042 mmol) were added. The mixture was degassed for 10 minutes beforeheating at 105° C. for 17 hours. The reaction mixture was quenched withwater and extracted with EtOAc (3×10 mL), dried with Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by columnchromatography on silica eluting with 0 to 10% MeOH in DCM to give thetitle compound, which was then treated with HCl (1.1 eq., 0.5M) to formthe HCl salt (107 mg, 21%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (d, J=6.8Hz, 1H), 8.24 (dd, J=6.4,3.1 Hz, 1H), 7.94 (s, 1H), 7.82-7.25 (m, 7H),7.19 (dd, J=8.4, 1.7 Hz, 1H), 6.83 (s, 1H), 6.32 (d, J=7.1 Hz, 1H), 4.92(t, J=6.7 Hz, 1H), 4.44 (d, J=10.2 Hz, 1H), 4.21 (d,J=10.1 Hz, 1H),3.58-3.37 (m, 1H), 2.75 (d, J=13.2 Hz, 1H), 2.30-2.16 (s, 3H).

LC/MS Method 3: ESI MH⁺ 572, retention time 1.86 minutes.

Example 64

(6R,12R)-3,10-dibromo-2-chloro-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

N-Bromosuccinimide (19 mg, 0.11 mmol) was added to a solution of Example23 (35 mg, 0.08 mmol) in DMF (3 mL) at room temperature. The reactionwas left to stir overnight. Further N-bromosuccinimide (19 mg, 0.11mmol) was added and the reaction mixture heated at 80° C. for 2 hours.The reaction mixture was cooled and concentrated in vacuo to a yellowoil, azeotroping with heptane to remove excess DMF. The crude materialwas purified by chromatography on silica, eluting with 0-50% EtOAc inhexanes to afford a clear oil. The material was freeze-dried(MeCN/water) to afford the title compound as a white solid (20 mg, 42%yield). ¹H NMR: (DMSO-d⁶, 400 MHz) δ: 2.66 (d, J=12.4 Hz, 1H), 3.10 (s,3H), 3.18 (dt, J=25.0, 8.3, 4.5 Hz, 1H), 5.93 (d, J=3.6 Hz, 1H), 6.10(d, J=4.6 Hz, 1H), 7.31 (t, J=74.1 Hz, 1H), 7.62 (d, J=9.3 Hz, 1H), 7.65(d, J=19.5 Hz, 1H), 7.70 (s, 1H), 8.11 (s, 1H). LC/MS Method 5 RT 2.87mins, m/z 584 and 586.

Example 65

(6R,12R)-2,8,10-trichloro-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

N-Chlorosuccinimide (21 mg, 0.16 mmol) was added to a solution ofExample 19 (43 mg, 0.12 mmol) in DMF (3 mL) at RT. The reaction wasstirred at 60° C. for 6 hours. The reaction mixture was cooled andconcentrated in vacuo to a yellow oil, azeotroping with heptane toremove the DMF. The crude material was subjected to chromatography onsilica (0-50% EtOAc in hexanes) and evaporated to afford a clear oil.The material was freeze-dried (MeCN/water) to afford the title compoundas an off white solid (9 mg, 17% yield). ¹H NMR: (DMSO-d6, 400 MHz) δ:2.35 (d, J=11.8 Hz, 1H), 3.00 (dt, J=16.0, 8.0, 4.0 Hz, 1H), 5.00 (d,J=3.7 Hz, 1H), 5.92 (d, J=4.4 Hz, 1H),), 7.20 (dd, J=8.6, 2.0 Hz, 1H),7.26 (t, J=73.9 Hz, 1H), 7.29 (d, J=4.1 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H),7.50 (s, 1H), 7.60 (d, J=7.6 Hz, 1H). LC/MS Method 5 RT 2.60 mins (pH10), m/z 417

Example 66

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4-methylpyrimidin-5-yl]-7,14-dihydro-7,14-methanopyrido[1′,2′:1,2]imidazo[4,5-d][2]benzazocin-5(6H)-one

Intermediate 112 (150 mg, 0.29 mmol), Na₂CO₃(s) (0.15 g, 1.45 mmol) and2,2-dichloro-1,1,3,3-tetracyclohexyl-1λ⁵,3λ⁵-diphospha-2-palladacyclohexane(0.02 g, 0.02 mmol) were suspended in degassed anhydrousdimethylacetamide (3.0 mL) in a 25 mL pressure vessel. The vessel wassealed and degassed thoroughly under vacuum then placed under anatmosphere of nitrogen. This process was twice repeated then the vesselwas evacuated and charged with 3 bar CO gas. The mixture was heated to150° C. overnight whereon the internal pressure reached 5 bar. Oncooling to room temperature, the mixture was thoroughly evacuated,diluted with EtOAc (20 mL) and filtered over a pad of celite, washingthe filter cake with further EtOAc (2×50 mL). The filtrate was washedwith water (25 mL) and the aqueous phase re-extracted with EtOAc (2×50mL). The combined organic phase was washed with brine (50 mL), dried(MgSO₄), filtered and concentrated in vacuo to give the crude product(165 mg) as a brown glass. Column chromatography (C18, biotage isolera,30 μ) eluting with 0 to 45% acetonitrile in water spiked with 0.1%formic acid afforded the racemic target (30 mg, 19%) as a tan solid.

Preparative chiral SFC employing a Chiralcel OD-H 25 cm eluting with 15%Methanol: 85% CO₂ eluting at 15 ml/min, gave the desired enantiomereluting at 4.88 minutes. Freeze drying from 1:1 MeCN-water afforded thetitle compound (6.9 mg, 5%, 92% chiral purity) as a colourless solid. ¹HNMR (500 MHz, DMSO-d₆) 1H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J=6.4 Hz,1H), 8.69 (s, 1H), 8.23 (dd, J=7.9, 1.4 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H),7.64 (d, J=11.1 Hz, 1H), 7.44 (t, J=75.0 Hz, 1H), 7.41 (d, J=7.6 Hz,1H), 7.37 (t, J=8.0 Hz, 1H), 5.13 (d, J=6.3 Hz, 1H), 5.11 (s, 1H), 4.68(t, J=6.4 Hz, 1H), 2.43-2.39 (m, 1H), 2.37 (s, 3H), 1.53 (s, 6H). LCMSMethod 6: MH+m/z 510, RT 2.37 min

Example 67

(7R,14R)-1-(difluoromethoxy)-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Example 11 (350 mg, 0.933 mmol) andIntermediate 100 (642 mg, 1.86 mmol), according to a method involvingthe same procedural steps as those described for Example 20. The crudeproduct was purified by flash chromatography (SiO₂, 0 to 100% EtOAc inDCM and then 1 to 12% MeOH in EtOAc) to give the title compound (305 mg,59%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.13 (d, J=6.8 Hz, 1H), 8.68 (s, 2H),8.22 (q, J=4.5 Hz, 1H), 7.73-7.64 (m, 1H), 7.60 (dd, J=1.9, 0.7 Hz, 1H),7.57-7.38 (m, 4H), 6.34 (d, J=7.0 Hz, 1H), 4.88 (t, J=6.7 Hz, 1H),4.39-4.29 (m, 2H), 4.17-3.96 (m, 2H), 3.60-3.39 (m, 1H), 2.73 (d, J=13.3Hz, 1H). LCMS basic Method 5 (ES+) RT 1.87 min, 557 (M−H)⁻

Example 68

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Example 10 (75 mg, 0.19 mmol) andIntermediate 100 (138 mg, 0.40 mmol), according to a method involvingthe same procedural steps as those described for Example 20. The crudeproduct was purified by flash chromatography (SiO₂, 0 to 100% EtOAc inDCM and then 1 to 12% MeOH in EtOAc) to obtain the title compound (61mg, 53%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.06 (d, J=6.8 Hz, 1H), 8.49 (d,J=1.7 Hz, 2H), 8.16 (dd, J=6.0, 3.4 Hz, 1H), 7.59-7.28 (m, 5H), 6.26 (d,J=7.0 Hz, 1H), 4.82 (t, J=6.8 Hz, 1H), 4.28 (d, J=10.3 Hz, 2H), 4.06 (d,J=10.1 Hz, 2H), 3.41 (dd, J=13.5, 6.8 Hz, 1H), 2.66 (d, J=13.4 Hz, 1H).LCMS Method 5: (ES+) RT 1.96 min, 575 (M−H)⁻

Example 69

(7R,14R)-1-(difluoromethoxy)-11-{2-[(1 s ,5 s)-3 ,7-dioxa-9-azabicy clo[3.3.1]non-9-yl]pyrimidin-5-yl}-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Example 10 (75 mg, 0.19 mmol) and[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-3,7-dioxa-9-azabicyclo[3.3.1]nonane(126 mg, 0.38 mmol), by a palladium catalysed Suzuki coupling accordingto a method involving the same procedural steps as those described forExample 20. The crude compound was purified by preparative reverse phaseHPLC to afford the title compound (5 mg, 5%). ¹H NMR (400 MHz, DMSO-d₆)δ 9.14 (d, J=6.9 Hz, 1H), 8.57 (d, J=1.7 Hz, 2H), 8.24 (dd, J=5.6, 3.9Hz, 1H), 7.65-7.56 (m, 1H), 7.54-7.42 (m, 4H), 6.33 (d, J=7.1 Hz, 1H),4.90 (t, J=6.6 Hz, 1H), 4.53 (s, 2H), 4.03 (d, J=11.3 Hz, 4H), 3.82-3.74(m, 4H), 3.48 (dt, J=13.5, 7.0 Hz, 1H), 2.74 (d, J=13.4 Hz, 1H). LCMSbasic Method 5 (ES+) RT 1.79 min, 565 (M+H)⁺

Example 70

(7R,14R)-1-(difluoromethoxy)-11-[2-methyl-4-(methylsulfonyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)one

(1-bromo-4-methanesulfonyl-2-methylbenzene (483 mg, 1.86 mmol),bis(pinacolato)diboron (525 mg, 2.0 mmol), and potassium acetate (369mg, 3.7 mmol) were dissolved in 1,4-dioxane (15 mL) and the mixturedegassed thoroughly with nitrogen.1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (38 mg, 0.05 mmol) was then added and themixture heated for 2.5 hours under nitrogen. The reaction mixture wasseparated between EtOAc (25 mL) and water (25 mL). The organic layer waspassed through a phase separator and evaporated in vacuo.

The crude product was engaged in a Suzuki reaction with Example 11 (350mg, 0.93 mmol), tricyclohexylphosphonium tetrafluoroborate (42 mg, 0.11mmol), tris(dibenzylideneacetone)-dipalladium(0) (56 mg, 0.060 mmol),and K₃PO₄ (592 mg, 2.79 mmol) in dioxane (5 ml) plus 2 drops of water.The mixture was heated in microwave for 18 hours at 110 degrees. Afterthis time the reaction mixture was separated between EtOAc (25 mL) andwater (25 mL) and the organic layer was passed through a phase separatorand evaporated in vacuo. The resultant residue was then purified byflash chromatography (SiO₂, 0 to 100% EtOAc in DCM and then 1 to 10%MeOH in EtOAc) to obtain mostly pure product (350 mg as brown solid 90%pure). Further purification by flash chromatography on silica gel 1-10%MeOH in DCM gave the title compound as off white powder (45 mg, 10%).

¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (d, J=6.9 Hz, 1H), 8.31-8.18 (m, 1H),7.89 (d, J=2.0 Hz, 1H), 7.87-7.65 (m, 2H), 7.59-7.38 (m, 4H), 7.45 (t,J=73 Hz, 1H), 7.36-7.15 (m, 1H), 6.31 (d, J=7.1 Hz, 1H), 4.89 (t, J=6.7Hz, 1H), 3.49 (dt, J=13.6, 7.1 Hz, 1H), 3.26 (s, 3H), 2.74 (d, J=13.4Hz, 1H), 2.30 (s, 3H). LCMS basic Method 5 (ES+) RT 1.83 min, 510(M+H)⁺.

Example 71

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 113 (650 mg, 0.97 mmol) was dissolved in tetrahydrofuran (6mL) and treated with a solution of tetrabutylammonium fluoride (1M inTHF, 2.90 mL, 2.90 mmol) dropwise and the reaction stirred at roomtemperature for 2 hours. The mixture was evaporated in vacuo andseparated between water and DCM. The organic phase was evaporated invacuo and treated with 2M HCl (aq) (20 mL) and THF (5 mL). The reactionwas stirred overnight and a further 20 mL of 2M HCl (aq) added. After afurther 18 hours the reaction mixture was diluted with water (75 mL) andthen evaporated in vacuo to remove volatiles. The aqueous was washedwith DCM (4×50 mL) to remove impurities and then the solution was thenmade basic with saturated sodium carbonate solution and extracted intoDCM (2×75 mL). The combined organics were washed with water (50 mL)dried (sodium sulphate), filtered and evaporated in vacuo. The solid wasthen dissolved in 0.5N HCl (aq) and freeze dried to afford the titlecompound as the HCl salt. (332 mg, 70%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (d, J=6.9 Hz, 1H), 8.48 (s, 1H), 8.25(dt, J=8.6,4.3 Hz, 1H), 8.17 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.52 (m,4H), 7.40-7.32 (m, 1H), 6.37 (d, J=7.1 Hz, 1H), 4.97 (t, J=6.8 Hz, 1H),3.58-3.43 (m, 1H), 2.78 (d, J=13.4 Hz, 1H), 2.50 (s, 3H), 1.65 (s, 6H).LCMS basic Method 5 (ES+) RT 1.62 min, 491 (M+H)⁺

Example 72

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 115 (154 mg, 0.21 mmol) was dissolved in a solution of 4MHCl in dioxane (10 mL) and stirred for 3 hours at room temperature.After this time the mixture was evaporated in vacuo and separatedbetween EtOAc (50 mL) and sodium carbonate (50 mL), the aqueous layerwas extracted with EtOAc (50 mL) and the combined organics were dried(though a phase separator) and evaporated in vacuo. The crude compoundwas purified by preparative reverse phase HPLC to afford the titlecompound (27 mg, 27%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (d, J=6.8 Hz,1H), 9.02 (s, 2H), 8.23 (dd, J=6.0,3.4 Hz, 1H), 7.80-7.65 (m, 3H), 7.59(dd, J=8.5, 1.8 Hz, 1H), 7.55-7.41 (m, 2H), 6.36 (d, J=7.1 Hz, 1H), 4.90(t, J=6.8 Hz, 1H), 3.49 (dt, J=13.9, 7.1 Hz, 1H), 2.75 (d, J=13.4 Hz,1H), 2.10 (s, 2H), 1.46 (s, 6H). LCMS basic Method 5 (ES+) RT 1.30 min,477.2 (M+H)⁺

Example 73

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 116 was dissolved in a mixture of dioxane (5 mL) and 4M HClin dioxane (5 mL). The mixture was stirred for 3 hours at roomtemperature before being evaporated in vacuo. The reaction mixture wasthen separated between EtOAc (25 mL) and 1M HCl (20 mL). The acid layermade basic with saturated sodium carbonate solution and extracted withDCM (3×25 mL). The combined organic layers were dried (phase separator)and evaporated in vacuo to afford the title compound as an off whitesolid (25 mg, 40% over two steps). ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (d,J=6.9 Hz, 1H), 8.92 (d, J=1.7 Hz, 2H), 8.24 (p, J=4.2 Hz, 1H), 7.71-7.60(m, 1H), 7.58-7.46 (m, 4H), 6.35 (d, J=7.0 Hz, 1H), 4.92 (t, J=6.8 Hz,1H), 3.50 (dt, J=13.5, 7.0 Hz, 1H), 2.75 (d, J=13.4 Hz, 1H), 2.15 (s,2H), 1.48 (s, 6H). LCMS basic Method 5 (ES+) RT 1.45 min, 495.2 (M+H)⁺

Example 74

2-{5-[(7R,14R)-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

Intermediate 119 (150 mg, 0.3991 mmol),2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(105 mg, 0.3976 mmol), cesium carbonate (0.260 g., 0.797 mmol),tris(dibenzylideneacetone)dipalladium(0) (18.3 mg., 0.020 mmol), andtricyclohexylphosphonium tetrafluoroborate (17.8 mg., 0.0479 mmol) weredissolved in a degassed mixture of 1,4-dioxane (2 mL) and water (0.5mL). The reaction mixture was heated for 3 hours at 105° C. The mixturewas cooled to room temperature and water was added. The mixture wasextracted with ethyl acetate, the combined organic layers dried overmagnesium sulfate, filtered and concentrated in vacuo. The crude productwas purified by preparative HPLC-LCMS (basic conditions; Gr 5-70(NH₄)₂CO₃) to afford 36 mg (19%) of the title compound as a white solid.LCMS Method 3 (ES+) RT 1.76 min., 478.2 (M+H)+.

Example 75

2-{5-[(5R or 5S,7R,14R)-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from Intermediate 120 (40 mg, 0.106mmol) and2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-olaccording to a method involving the same procedural steps as thosedescribed for Example 20, to afford the title compound 24 mg (47%).

¹H NMR (400 MHz, CDCl₃) δ ppm 8.91 (s, 2H), 7.91 (d, 1H, J=9.2 Hz), 7.46(m, 2 H), 7.27 (t, 1H, J=8.3 Hz), 7.15 (m, 2H), 6.74 (t, 1H, J=73.8 Hz),6.29 (d, 1H, J=7.5 Hz), 4.73 (d, 1H, J=5.8 Hz), 4.68 (s, 1H), 3.18 (m,1H), 2.90 (q, 1H, J=6.3 Hz), 2.47 (d, 1H, J=12.4 Hz), 2.42 (s, 1H), 1.64(s, 6H), 1.41 (d, 3H, J=6.4 Hz). LCMS Method 3 (ES+) RT 2.36 min., 478.2(M+H)⁺.

Example 76

2-{5-[(5R or5S,7R,14R)-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from Intermediate 121 (40 mg, 0.106mmol) and2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-olaccording to a method involving the same procedural steps as thosedescribed for Example 20, to afford the title compound 25 mg (49%).

¹H NMR (400 MHz, CDCl₃) 8 ppm 8.94 (s, 2H), 7.87 (d, 1H, J=8.4 Hz), 7.56(d, 1H, J=1.4 Hz), 7.45 (dd, 1H, J=8.5, 1.7 Hz), 7.23 (t, 1H, J=8.1 Hz),7.09 (d, 1H, J=8.1 Hz), 7.02 (d, 1H, J=7.6 Hz), 6.77 (t, 1H, J=73.5 Hz),6.25 (d, 1H, J=7.6 Hz), 4.71 (m, 2H), 4.50 (q, 1H, J=7.5 Hz), 3.24 (ddd,1H, J=13.0, 7.5, 6.0 Hz), 2.61 (d, 1H, J=12.6 Hz), 2.01 (s, 1H), 1.65(s, 6H), 0.45 (d, 3H, J=7.4 Hz). LCMS Method 4 (ES+) RT 1.83 min., 478.2(M+H)⁺.

Example 77

1-[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

To a solution of Example 74 (30 mg, 0.063 mmol) in dichloromethane (0.5mL) was added pyridine (50 μL). The reaction mixture was cooled to 0° C.and acetic anhydride (0.5 mL) was added dropwise. The reaction mixturewas stirred overnight at room temperature. Water and solid NaHCO₃ wereadded and the mixture was extracted with dichloromethane. The combinedorganic layers were dried over MgSO₄, filtered and concentrated in vacuoto afford 24 mg (74%) of the title compound as a mixture ofdiastereomers. LCMS Method 3 (ES+) RT 3.53 min and 3.70 min., 520.3(M+H)⁺.

Example 78

1-[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

To a solution of Intermediate 128 1 (300 mg, 0.48 mmol) in methanol (7mL) was addedp-toluenesulfonic acid monohydrate (460 mg, 2.42 mmol). Thereaction mixture was stirred at room temperature for 4 hours. Themethanol was evaporated at in vacuo. The residue was dissolved in DCM (2mL). The organic layer was washed with a saturated solution of NaHCO₃(3×1 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude material was purified by preparative basic reverse phase HPLC-MSto afford 150 mg (61%) of the title compound as a white powder.

LCMS Method 3 basic (ES+) RT 3.71 min., 506 (M+H)⁺.

LCMS Method 4 acidic (ES+) RT 3.88 min., 506 (M+H)⁺.

Example 79

2-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

Intermediate 129 (80 mg, 0.135 mmol) was treated in accordance with thesynthetic procedure described for Example 78. The crude material waspurified by preparative basic reverse phase HPLC-MS affording 2.4 mg(4%) of the title compound as an off white solid.

LCMS Method 3 basic (ES+) RT 3.83 min., 478.1 (M+H)⁺.

Example 80

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-(methylsulfonyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

Example 16 (14.3 mg, 0.03 mmol) was dissolved in DCM (0.6 mL). Thesolution was cooled at −60° C. before successive addition oftriethylamine (8.34 μL, 0.06 mmol) and a solution of methanesulfonylchloride (2.31 μL, 0.03 mmol) in DCM (20 μL). The solution was slowlywarmed to room temperature overnight. The reaction was quenched byaddition of a saturated aqueous solution of NH₄Cl (1 mL) and diluted byDCM (2 mL). The organic layer was washed with successively a saturatedsolution of NH₄Cl (2×1 mL) and a saturated solution of NaHCO₃ (2×1 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by reverse phase basic preparative HPLC-MS yielding to 11 mg(66%) of the title compound as an off white solid.

LCMS Method 3 (ES+) RT 4.07 min., 560.13 (M+H)⁺.

LCMS Method 4 (ES+) RT 4.24 min., 560.13 (M+H)⁺.

Example 81

2-{5-[(7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

To a solution of Intermediate 130 (7 mg, 0.011 mmol) in methanol (0.5mL) was added p-toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) andthe resulting slurry was stirred overnight. The reaction mixture wasthen diluted with dichloromethane and aqueous saturated solution ofNaHCO₃. The two phases were separated and the aqueous layer furtherextracted with dichloromethane. The combined organic extracts were driedover magnesium sulphate, filtered and concentrated under reducedpressure. The crude material was purified by basic reverse phaseHPLC-MS, yielding to 2.8 mg (49%) of the title compound in a 83/17 ratioof diastereoisomers.

LCMS Method 3 (ES+) RT 4.1 min., 532.2 (M+H)⁺.

LCMS Method 4 (ES+) RT 2.66 min., 532.2 (M+H)⁺.

Example 82

2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

or

2-{5-[(5S,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

To a solution of Intermediate 131 (4.8 mg, 0.0074 mmol) in methanol (0.5mL) was added p-toluenesulfonic acid monohydrate (7.1 mg, 0.037 mmol).The reaction mixture was stirred overnight. The methanol was evaporatedat room temperature in vacuo. The crude material was purified by basicreverse phase HPLC-MS, yielding 3.9 mg (99%) of the title compound as apale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (m, 2H), 7.17 (s, 1H),7.03 (m, 4H), 6.86 (m, 2H), 6.38 (m, 1H), 5.32 (m, 1H), 4.61 (m, 1 H),4.51 (m, 1H), 3.48 (m, 1H), 2.83 (m, 1H), 2.41 (m, 1H), 1.62 (m, 6H).LCMS Method 3 (ES+) RT 2.33 min., 532.2 (M+H)⁺. LCMS Method 4 (ES+) RT2.35 min., 532.2 (M+H)⁺.

Example 83

2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

or

2-{5-[(5 S ,7 R ,14 R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

To a solution of Intermediate 132 (23 mg) in methanol (1 mL) was addedp-toluenesulfonic acid monohydrate (34 mg). The reaction mixture wasstirred overnight. The methanol was evaporated at room temperature invacuo. The crude material was purified by basic reverse phase HPLC-MS,yielding 15 mg (80%) of the title compound as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 8.93 (m, 2H), 7.97 (m, 1H), 7.51 (m, 2H), 7.33(m, 2 H), 7.23 (m, 1H), 6.77 (m, 1H), 6.32 (m, 1H), 4.91 (m, 1H), 4.68(m, 1H), 3.39 (m, 1 H), 3.21 (m, 1H), 2.67 (m, 1H), 2.54 (m, 1H), 1.63(m, 6H). LCMS Method 4 (ES+) RT 2.33 min., 532.2 (M+H)⁺. LCMS Method 3(ES+) RT 2.59 min., 532.2 (M+H)⁺.

Example 84

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-1-oxidopyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of Example 1 (10 mg, 0.02 mmol) in DCM (0.5 mL) were addedm-chloroperbenzoic acid (57 mg, 0.33 mmol) and NaHCO₃ (14 mg; 0.16mmol). The reaction mixture was stirred at ambient temperature for 24hours. The mixture was diluted with DCM (1 mL) and washed with asaturated aqueous solution of NaHCO₃ (1 mL) and brine (1 mL), andconcentrated in vacuo. The crude material was purified by LC-2D MSchromatography in acidic mode (formic acid) to give 0.5 mg (5%) of thetitle compound. LCMS Method 4 (ES+) RT 5.30 minutes, 512.2 (M+H)⁺.Analytical method used for the separation:

semi preparative HPLC column: Sunfire prep C18 5 μm 10×150 mm columnGradient: 98% Solvent A (Water, acetonitrile, Formic acid (95/5/0.5,v/v/v)) to 90% Solvent B (Acetonitrile, Formic acid (99.3/0.7, v/v)) in9 minutes with a hold at 90% B of 4 minutes.

Flow rate: 7 ml/min

Example 85

(7R,14R)-1-(difluoromethoxy)-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 11 (350 mg, 0.93 mmol) and crude Intermediate 133 (1.00 g, 2.8mmol) were dissolved in dioxane (10 mL) and K₃PO₄ (592 mg, 2.79 mmol) inwater (1 mL) was added, degassed and placed under nitrogen before addingtris(dibenzylideneacetone)dipalladium(0) (44 mg, 0.047 mmol) andtricyclohexylphosphonium tetrafluoroborate (42 mg, 0.11 mmol). Themixture was heated to 105° C. under nitrogen for 18 hours. The mixturewas partitioned between EtOAc and water (50 mL each), separated and theorganic phase dried (magnesium sulfate), filtered and concentrated invacuo. The residue was purified by chromatography (silica 25 g, 0-15%gradient of methanol in dichloromethane) to give the title compound asan off-white solid (240 mg, 45% yield). LC/MS Method 3: RT 1.90 mins,m/z 573. ¹H NMR (300 MHz, DMSO-d₆) δ 9.13 (d, J=6.8 Hz, 1H), 8.31-8.13(m, 2H), 7.89-7.24 (m, 6H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 6.30 (d, J=7.0Hz, 1H), 4.88 (t, J=6.7 Hz, 1H), 4.31 (d, J=10.5 Hz, 2H), 4.08 (d,J=10.2 Hz, 2H), 3.48 (dt, J=13.6, 7.0 Hz, 1H), 2.73 (d, J=13.4 Hz, 1H),2.29 (s, 3H).

Example 86

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)one

The title compound was prepared from Example 10 and Intermediate 133 inaccordance with the synthetic procedure described for Example 85 toafford an off white solid. ¹H NMR (500 MHz, Chloroform-d) δ 8.44 (d,J=7.9 Hz, 1H), 8.09 (br s, 1H), 7.53-7.41 (m, 2H), 7.40-7.33 (m, 1H),7.16 (br s, 1H), 6.77 (t, J=72.6 Hz, 1H), 6.32 (d, J=7.0 Hz, 1H), 4.97(s, 1H), 4.52 (d, J=10.1 Hz, 2H), 4.24 (d, J=10.2 Hz, 2H), 3.57-3.40 (m,1H), 2.87 (d, J=13.3 Hz, 1H), 2.26 (s, 3H). LCMS; Method 8, RT =2.78min, m/z=591.0.

Example 87

(7R,14R)-1-(difluoromethoxy)-11-{6-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-2-methylpyridin-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 135 (500 mg, 1.39 mmol) and Example 11 (300 mg, 0.80 mmol)were treated in accordance with the synthetic procedure described forExample 86. After purification by preparative HPLC, the title compoundwas obtained as a white solid (30 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 9.14(d, J=6.8 Hz, 1H), 8.24 (dd, J=5.9, 3.5 Hz, 1H), 7.76-7.24 (m, 7H), 7.13(dd, J=8.4, 1.7 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 6.29 (d, J=7.1 Hz, 1H),4.88 (t, J=6.7 Hz, 1H), 4.24 (d, J=9.6 Hz, 2H), 3.98 (d, J=9.6 Hz, 2H),3.48 (dt, J=13.5, 6.9 Hz, 1H), 2.73 (d, J=13.3 Hz, 1H), 2.28 (s, 3H).LC/MS Method 3: RT 2.02 minutes, m/z 572.

Example 88

(6R,12R)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine

Intermediate 136, (1.90 g, 3.35 mmol) was dissolved in dry THF (20 mL),cooled to 0° C. under nitrogen and N,N-diisopropylethylamine (0.76 mL,4.4 mmol) and then methanesulfonyl chloride (0.31 mL, 4.0 mmol) wereadded and the mixture stirred for 1 hour until TLC analysis showsconversion to the faster running mesylate. Sodium ethoxide 21%wtsolution in ethanol (2.5 mL, 6.7 mmol) was added and the mixture allowedto warm to ambient temperature with stirring overnight. A furtherportion of the sodium ethoxide solution (2.5 mL) was added and stirredfor another 48 hours. The mixture was concentrated in vacuo, thenpartitioned between dichloromethane and aqueous sodium bicarbonatesolution (75 mL each). The organic phase was dried (sodium sulfate),filtered and concentrated in vacuo. Purification by chromatography(silica, isohexane/DCM 0-100% gradient, then 0-10% ethyl acetate in DCM)afforded the title compound as a pink solid (670 mg, 55% yield). ¹H NMR(300 MHz, DMSO-d₆) δ 7.77-7.46 (m, 2H), 7.49 (t, 1H, J_(H-F)=73.4 Hz),7.35 (d, J=2.1 Hz, 1H), 7.31-7.11 (m, 2H), 7.01-6.89 (m, 1H), 6.01 (d,J=5.3 Hz, 1H), 4.97 (d, J=5.0 Hz, 1H), 3.50-3.34 (m, 1H), 2.66 (d,J=12.2 Hz, 1H). LC/MS Method 3: RT 2.16 minutes, m/z 365/367.

Example 89

2-{5-[(6R,12R)-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

Example 88 (100 mg, 0.25 mmol) andtris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol),tricyclohexylphosphonium tetrafluoroborate (13 mg, 0.033 mmol) and2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (116mg, 0.44 mmol) were added to a microwave tube, dioxane (3 mL) addedfollowed by K₃PO₄ (174 mg, 0.82 mmol) dissolved in water (3004) wasadded and the vessel placed under nitrogen. The mixture was heated to140° C. under nitrogen in the microwave (3 bar pressure) until LCMSshows reaction to be complete (typically 1 hour). Purification bychromatography (silica, 0 to 10% methanol gradient in dichloromethane)followed by additional column chromatography (silica, EtOAc, 0 to 7%gradient of methanol) gave the title compound as an off white solid (105mg, 82% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (s, 2H), 7.82-7.35 (m,4H), 7.26 (t, J=8.1 Hz, 1H), 6.96 (dd,J=8.1, 4.2 Hz, 2H), 6.08 (d, J=5.3Hz, 1H), 5.13 (s, 1H), 5.06-4.97 (m, 1H), 3.47 (dt,J=12.2, 5.4 Hz, 1H),2.71 (d,J=12.3 Hz, 1H), 1.55 (s, 6H). LC/MS Method 3: RT 2.02 minutes,m/z 467.0.

Example 90 and Example 91

Example 90:(6R,7R,12S)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine7-oxide Example 91:(6R,7S,12S)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine7-oxide

Example 88 (1.00 g, 2.741 mmol) was dissolved in dichloromethane (15mL), saturated aqueous sodium bicarbonate solution (5 mL) was added andstirred vigorously, 3-meta-chloroperoxybenzoic acid (645 mg, 2.88 mmol,77%) was added and the mixture stirred for 2 hours. The layers wereseparated and the organic phase dried (sodium sulfate), filtered andconcentrated in vacuo. Purification by chromatography (silica,dichloromethane 0 to 5% methanol) gave the title compounds. The majordiastereoisomer, Example 90, eluting first (771 mg, 74%) and then theminor diastereoisomer, Example 91 (44 mg, 4%).

Example 90, Major diastereoisomer: ¹H NMR (300 MHz, Chloroform-d) δ 7.61(d, J=8.7 Hz, 1H), 7.54-7.42 (m, 2H), 7.37 (d, J=2.0 Hz, 1H), 7.32-7.15(m, 2H), 6.77 (dd, J=72.7, 71.8 Hz, 1H), 5.98 (d, J=5.4 Hz, 1H), 4.90(d, J=5.3 Hz, 1H), 3.70 (d, J=13.0 Hz, 1H), 3.43 (dt, J=13.1, 5.4 Hz,1H). LC/MS Method 3: RT 1.93 minutes, m/z 381.0/383.0.

Example 91, Minor diastereoisomer: ¹H NMR (300 MHz, Chloroform-d) δ7.73-7.60 (m, 2H), 7.47 (t, J=8.1 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H),7.25-7.15 (m, 2H), 6.77 (dd, J=72.7, 71.8 Hz, 1H), 5.95 (d, J=5.6 Hz,1H), 5.08 (d, J=6.3 Hz, 1H), 3.44 (dt, J=13.6, 6.0 Hz, 1H), 2.85 (d,J=13.5 Hz, 1H). LC/MS Method 3: RT 1.80 minutes, m/z 381.0/383.0.

Example 92

2-{5-[(6R ,7 R,12S)-11-(difluoromethoxy)-7-oxido-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

Example 90 (56 mg, 0.147 mmol) and2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester weretreated in accordance with the synthetic procedure described for Example89. Flash column chromatography (silica, 0 to 5% gradient of methanol indichloromethane) afforded the title compound as a pale brown solid (12mg, 17% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.98 (s, 2H), 7.79-7.60 (m,2H), 7.58-7.44 (m, 4H), 7.34 (q, J=4.3 Hz, 1H), 6.10 (d, J=4.7 Hz, 1H),5.22 (d, J=4.5 Hz, 1H), 5.05 (s, 1H), 3.51-3.30 (m, 2H), 1.47 (s, 6H).LC/MS Method 3: RT 1.59 minutes, m/z 483.0

Example 93

2-{5-[(6R,7S,125)-11-(difluoromethoxy)-7-oxido-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

Example 91 (44 mg, 0.15 mmol) and2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester weretreated in accordance with the synthetic procedure described for Example89. Flash column chromatography (silica, 0 to 5% gradient of methanol indichloromethane) afforded the title compound as a pale brown solid (15mg, 27% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.08 (s, 2H), 7.89-7.49 (m,6H), 7.40-7.23 (m, 1H), 6.08 (d, J=5.5 Hz, 1H), 5.46 (d, J=6.2 Hz, 1H),5.12 (s, 1H), 3.44 (dt,J=13.6, 6.0 Hz, 1H), 2.93 (d, J=13.8 Hz, 1H),1.55 (s, 6H). LC/MS Method 3: RT 1.56 minutes, m/z 483.0.

Example 94

(6R,12R)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine7,7-dioxide

Example 88 (240 mg, 0.66 mmol) treated in accordance with the syntheticprocedure described for Example 90/91 with 2eq of mCPBA. The titlecompound was obtained after chromatography as a white solid (196 mg, 76%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.75-7.60 (m, 3H), 7.56 (t, 1H, JHF=72.7 Hz), 7.53-7.45 (m, 1H), 7.41 (dd, J=2.1, 0.5 Hz, 1H), 7.26 (dd,J=8.7, 2.1 Hz, 1H), 6.12 (d, J=5.4 Hz, 1H), 5.61 (d, J=5.7 Hz, 1H), 3.75(dt, J=13.6, 5.8 Hz, 1H), 3.52 (d, J=13.6 Hz, 1H). LC/MS Method 3: RT1.86 minutes, m/z 397.0/399.0.

Example 95

2-{5-[(6R,12R)-11-(difluoromethoxy)-7,7-dioxido-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

Example 94 (198 mg, 0.50 mmol) and2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester weretreated in accordance with the synthetic procedure described for Example89 to give the title compound after chromatography as an off-white solid(90 mg, 36% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.08 (s, 2H), 7.91-7.79(m, 1H), 7.74-7.58 (m, 5H), 7.54-7.41 (m, 1H), 6.17 (d, J=5.4 Hz, 1H),5.63 (d, J=5.7 Hz, 1H), 5.13 (s, 1H), 3.87-3.70 (m, 1H), 3.56 (d, J=13.5Hz, 1H), 1.55 (s, 6H). LC/MS Method 3: RT 1.72 minutes, m/z 499.0.

Example 96

1-[5R,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

or

1-[(5S,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

To a solution of Example 76 (22 mg, 0.046 mmol) and pyridine (5 μL, 0.06mmol) in dichloromethane (0.5 mL), cooled at 0° C., was added aceticanhydride (460 μL; 4.6 mmol). The reaction was allowed to reach ambienttemperature and stirred overnight. The crude reaction mixture was pouredinto ice water (2 mL), before neutralisation by solid NaHCO₃. Theaqueous layer was extracted by ethyl acetate (2×2 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuum. The residue was taken up in di-isopropyl ether and concentratedin vacuum. The resulting solid was dissolved in 1-4 dioxane/water (1:1mixture, total volume 5 mL) before freeze drying to yield 21 mg (90%) ofthe title compound as a white solid. LCMS Method 3 (ES⁺): RT 2.18 min,[M+H]⁺=520.2

Example 97

1-[5R,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

Or

1-[5S,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

The title compound was prepared from Example 75 (2.3 mg, 4.8 μmop by themethod of Example 96. The crude material was purified by basic reversephase preparative HPLC-MS, yielding 2.1 mg (90%) of the title compoundas a colorless oil. LCMS Method 3 (ES+): RT 2.20 min, [M+H]⁺=520.2.

Example 98

(7R,14R)-10-fluoro-1-hydroxy-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 1 (300 mg, 0.61 mmol) was dissolved in dry tetrahydrofuran (10mL/mmol). The solution was cooled to 0° C. andsodiumbis(trimethylsilyl)amide (5 eq, 3.03 mmol) was added. The reactionmixture was stirred at 0° C. for 30 minutes and overnight at roomtemperature. The reaction mixture was cooled to 0° C. and quenched withwater (5 mL). Tetrahydrofuran was evaporated; the aqueous layer wasbrought to pH 6-7 by addition of 0.1N HCl and extracted with ethylacetate (3×10 mL). The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified over silica gel (5-10%MeOH in DCM), yielding 85 mg (31%) of the title compound as a whitesolid.

LCMS Method 3 (ES+): RT 1.64 min., [M+H]⁺=446.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10,56 (s, 1H), 8,97 (d, J=1,5 Hz, 2H), 8,93 (d, J=7,0 Hz,1H), 7,79 (dd, J1=8,0 Hz, J2=1,0 Hz, 1H), 7,71 (d, J=7,0 Hz, 1H), 7,63(d, J=11,5 Hz, 1H), 7,20 (t, J=8,0 Hz, 1H), 7,10 (dd, J1 =8,0 Hz, J2=1,2 Hz, 1H), 6,41 (d, J=7,0 Hz, 1H), 5,14 (s, 1H), 4,87 (t, J=6,9 Hz,1H), 3,42 (m, 1H), 2,68 (d, J=13,2 Hz, 1H), 1,56 (s, 6H).

Example 99

2-{5-[(7R,14R)-1-(difluoromethoxy)-5-methyl-5-oxido-7,14-dihydro-7,14-methano-5λ-4-benzimidazo[2,1-d][1,2,5]benzothiadiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

To a solution of Intermediate 142 (8 mg) in MeOH (5 mL) was addedp-toluene sulfonic acid monohydrate (18.6 mg, 0.1 mmol). The reactionmixture was stirred at ambient temperature overnight. The methanol wasevaporated and the residue was taken up in DCM (5 mL). The organic layerwas washed with a mixture of saturated aqueous sodium bicarbonatesolution and water 50/50 (3 mL). The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byreverse phase preparative LCMS yielding 3.7 mg (57%) of the titlecompound as a pale yellow solid. LCMS Method 3 (ES+): RT 2.02 minutes,[M+H]+=512.1. ¹H NMR (300 MHz, MeOD-d₄) δ 9,04 (s, 2H), 7,99 (d, J=8.7Hz, 1H), 7.94 (d, J=8,6 Hz, 1H), 7.84 (dd, J1 =6.4 Hz, J2=2.4 Hz, 1H),7.75 (s, 1H), 7.69 (d, J=6.4 Hz, 1H), 7.68 (s, 1H), 7.36 (t, J=72.6 Hz,1H), 6.87 (d, J=7.9 Hz, 1H), 5.34 (d, J=5.1 Hz, 2H), 3.61 (m, 1H), 3.56(s, 3 H), 2.95 (d, J=13.2 Hz, 1H), 1.65 (s, 6H).

Example 100

(7R,14R)-1-(difluoromethoxy)-11-{6-[1-(methylsulfonyl)cyclopropyl]pyridin-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 11 (30 mg, 0.08 mmol), bis(pinacolato)diboron (25 mg, 0.096mmol), potassium acetate (24 mg, 0.24 mmol), tricyclohexylphosphoniumtetrafluoroborate (7 mg, 0.019 mmol) andtris(dibenzenylideneacetone)dipaladium(0) (7 mg, 0.008 mmol) were mixedin degassed dioxane (1 mL). The reaction mixture was stirred at 80° C.for 24 hours. Intermediate 143 (29 mg, 0.08 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4 mg, 0.006mmol), cesium carbonate (52 mg, 0.16 mmol) and water (0.11 mL) wereadded and the reaction mixture was stirred at 95° C. for 2 hours. Thereaction mixture was concentrated in vacuum and the crude was purifiedby reverse phase basic preparative LCMS yielding 8 mg (19%) of the titlecompound as an white solid. LCMS Method 3 (ES+): RT 1,19 min,[M+H]+=537.1.

¹H NMR (300 MHz, MeOD-d₄) δ 8.90 (s, 1H), 8.36 (dd, J=7.0, 1.3 Hz, 1H),8.23 (dd, J=8.2, 1.7 Hz, 1H), 8.02 (s, 1H), 7.88 (m, 3H), 7.55 (m, 2H),7.35 (t, J=72.8 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H), 5.27 (d, J=6.7 Hz, 1H),3.67 (m, 1H), 3,04 (s, 3H), 3.01 (d, J=13.6 Hz, 1H), 1.87 (s, 2H), 1.58(m, 2H).

Example 101

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 149 (55 mg, 0.14 mmol),2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (75mg, 0.27 mmol), tricyclohexylphosphonium tetrafluoroborate (12 mg, 0.033mmol), tris(dibenzenylideneacetone)dipaladium(0) (12 mg, 0.014 mmol),potassium triphosphate (60 mg, 0.27 mmol) and water (0,22 mL) were mixedin degassed 1,4-dioxane (2.2 mL). The reaction mixture was stirred at130° C. under nitrogen for 3 hours. The crude reaction mixture waspartially concentrated and purified over silica gel (Heptane:EtOAc 75 to100%), yielding 63 mg (93%) of the title compound as a white solid. LCMSMethod 3 (ES+): RT 2.19 min, [M+H]⁺=506.2. ¹H NMR (300 MHz, CDCl₃) δ8.96 (s, 2H), 8.55 (d, J=8.0 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.82 (s,1H), 7.54 (d, J=7.8 Hz, 1H), 7.49 (t, J=8.5 Hz, 1H), 7.35 (d, J=7.8 Hz,1H), 6.90 (t, J=72.7 Hz, 1H), 6.23 (d, J=6.0 Hz, 1H), 4.70 (bs, 1H),3.46 (m, 4H), 3.14 (d, J=13.5 Hz, 1H), 2.22 (s, 3H), 1.68 (s, 6H).

Example 102

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 148 (29 mg, 0.08 mmol)and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester(41 mg, 0.15 mmol) following the procedure used for Example 101. Thecrude material was purified by reverse phase basic preparative HPLC,yielding 6 mg (13%) of the title compound as a white solid. LCMS Method3 (ES+): RT 2.05 minutes, [M+H]¹=492. ¹H NMR (300 MHz, CDCl₃) δ 8.95 (s,2H), 8,48 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.66(d, J=8.3 Hz, 1H), 7.55 (t, J=8.3 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 6.93(t, J=72.8 Hz, 1H), 6.52 (d, J=4.3 Hz, 1H), 3.67 (s, 1H), 3.50 (m, 1H),3.09 (d, J=13.3 Hz, 1H), 2.31 (s, 3H), 1,68 (s, 6H).

Example 103

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of Intermediate 150 (13 mg, 0.022 mmol) in DMF (0.5 mL),at 0° C., was added sodium hydride (60% mineral oil) (0.88 mg, 0.022mmol) at 0° C. and stirred at room temperature for 30 minutes.Iodomethane (3 mg, 0.022 mmol) was then added and the reaction mixturewas stirred at room temperature overnight. The reaction mixture waspurified by reverse phase basic preparative HPLC-MS to yield 7 mg (0.012mmol, 53%) of a white solid. The intermediate was added to a solution ofDCM/trifluoroacetic acid (1:1, 0.25 mL). The reaction mixture wasstirred at ambient temperature for 1 hour before addition of a saturatedaqueous solution of NaHCO₃ (1 mL). The aqueous layer was extracted byDCM (2×2 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified by reversephase basic preparative HPLC-MS, yielding 2.2 mg (38%) of the titlecompound as a beige solid. LCMS Method 3 (ES+): RT 1.99 minutes,[M+H]⁺=505.

Example 104

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4,6-dimethylpyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 1 (25 mg, 0.052 mmol) was dissolved in a 1:1 mixture of TFA/MeCN(0.53 mL) in a 4 mL glass vial. [Ir{dF(CF3)ppy}2(dtbpy)]PF₆ (1.175 mg,0.00105 mmol, Aldrich) and tert-butyl peroxyacetate (41.5 mg, 0.16 mmol,50% solution in mineral spirits, 3.0 eq., Aldrich) were then added. Themixture was degassed with argon for 5 minutes then irradiated with bluelight emitting diodes (460 nm visible light, OSRAM Oslon SSL 80royal-blue on Star, 1000 mA, ˜1 W) until UPLC-MS analysis indicatescomplete consumption of starting material (12 hours). The solvents wereremoved by evaporation to give an orange oil. Purification by reversephase preparative chromatography (acidic mode, gradient from 30% MeCN in0.1% TFA in water up to 95% MeCN) yielded the title compound as acolorless oil (5.8 mg, 21% yield). LCMS Method 4 (ES+): RT: 2.41 min,[M+H]+=524.2. LCMS Method 3 (ES+): RT: 2.21 min, [M+H]+=524.2. ¹H NMR(400 MHz, MeOD-d₄) δ 8.26 (t, J=4.7 Hz, 1H), 7.52 (d, J=9.9 Hz, 1H),7.42 (m, 3H), 7.05 (dd, J=73.6, 72.1 Hz, 1H), 6.43 (d, J=7.1 Hz, 1H),4.97 (d, J=6.7 Hz, 2H), 3.54 (s, 1H), 3.49 (m, 1H), 2,80 (d, J=13.6 Hz,1H), 2.37 (s, 3H), 2.17 (s, 3H), 1.59 (s, 6H).

Example 105 and Example 106

2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,14-dihydro-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-11-yl]pyrimidin-2-yl}propan-2-ol

and

2-{5-[(5S,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,14-dihydro-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-11-yl]pyrimidin-2-yl}propan-2-ol

Intermediate 155 (50 mg, 0.091 mmol) was dissolved in toluene (1 mL),cyanomethylenetributylphosphorane (100 μL, 0.1 mmol) was added. Theslurry was stirred overnight at 100° C. Additionalcyanomethylenetributylphosphorane (100 μL, 0.1 mmol) was added and thereaction mixture stirred overnight at 100° C. to complete the reaction.The solvent was evaporated and the crude partitioned into EtOAc (2 mL)and water (1 mL). The aqueous layer was extracted with EtOAc (2×1 mL).The combined organic layers were dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by reversephase basic HPLC-MS followed by reverse phase acid HPLC-MS purification.Each diastereoisomer was taken up in EtOAc (1 mL) and neutralized by asaturated solution of NaHCO₃ (1 mL). The aqueous layer was extractedwith EtOAc (2×1 mL). The organic layers were dried over MgSO₄, filteredand concentrated under reduced pressure to give the followingdiastereoisomers. 3 mg (6%) of Diastereomer A was isolated as whitesolid. LCMS Method 3 (ES+): RT 2.39 min., 533 (M+H)+. LCMS Method 4(ES+): RT 2.54 min., 533 (M+H)+. ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 2H),7.91 (m, 1H), 7.67 (m, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.28 (s, 1H),7.23 (d, J=7.8 Hz, 1H), 6.85 (m, 1H), 6.23 (m, 1H), 5.60 (d, J=4.4 Hz,1H), 5.49 (m, 1H), 4.70 (m, 1H), 3.20 (m, 1H), 3.00 (m, 1H), 1.66 (s,6H). 9 mg (19%) of Diastereomer B was isolated as off white solid. LCMSMethod 3 (ES+): RT 2.59 min., 533 (M+H)+. LCMS Method 4 (ES+): RT 2.76min., 533 (M+H)+. ¹H NMR (400 MHz, CDCl₃) δ 8.93 (m, 2H), 8.02 (m, 1H),7.54 (m, 2H), 7.35 (d, J=5.3 Hz, 2H), 7.29 (m, 1H), 6.79 (m, 1H), 6.40(m, 1H), 5.71 (m, 1H), 4.68 (m, 1H), 3.84 (m, 1H), 3.12 (m, 1H), 2.78(m, 1H), 1.65 (s, 6H).

General Procedure for the Late Stage Trifluoromethylation

To a solution of Example 1 (600 mg, 1.211 mmol) in degassed acetonitrile(1 ml) and TFA (1 ml)was added trifluoromethanesulfonyl chloride (65 μL,0.6045 mmol) followed by [Ir[DF(CF₃)PPY]₂(DTBPY)]PF₆ (4.5 mg, 0.0040mmol) under argon . The slurry was stirred overnight under blue lightemitting diodes (460 nm visible light, OSRAM Oslon SSL 80 royal-blue onStar, 1000 mA, ˜1 W). The reaction was performed in 6 vials of 100 mgportions of Example 1. The six crude mixtures were gathered and dilutedwith EtOAc (10 mL) and washed by a saturated solution of NaHCO₃ (2×5mL). The aqueous layer was back extracted by EtOAc (5 mL). The combinedorganic layers were dried over MgSO₄, filtered and concentrated underreduced. The residue was purified by reverse phase basic LCMS to afforda mixture of the desired isomers as an yellow solid (218 mg, 33% yield).

Example 107

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-12-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

1.1 mg (0.5%) of the title compound as an off white solid was isolatedfrom the above described mixture of diastereomers by LC-2D MSchromatography in acidic mode (formic acid) Method 14. LCMS Method/5(ES+) RT 5.82 min., 564 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (d,J=6.2 Hz, 1H), 8.86 (s, 1H), 8.75 (s, 1H), 8.10 (d, J=8.10, 1H) 8.06 (d,J=8.06 Hz, 1H), 7.51 (t, J=7.51 Hz, 1H), 7.44 (d, J=7.44 Hz, 1H), 7.14(dd, J=73.9, 72.3 Hz, 1H), 6.46 (d, J=7.3 Hz, 1H), 5.14 (s, 1H), 4.92(t, J=6.3 Hz, 1H), 3.51 (m, 1H), 2.67 (d, J=13.6 Hz, 1H), 1.54 (s, 6H).

Example 108

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-4-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

77.1 mg (35%) of the title compound as an off white solid was isolatedfrom the above described mixture of diastereomers by LC-2D MSchromatography in acidic mode (formic acid) Method 14 . LCMS Method/5(ES+) RT 5.90 min., 564 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (d,J=1.5 Hz, 2H), 8.85 (d, J=5.3 Hz, 1H), 7.90 (m, 1H), 7.71 (m, 2H), 7.54(m, 2H), 6.29 (d, J=7.2 Hz, 1H), 5.16 (m, 1H), 4.90 (t, J=5.8 Hz, 1H),3.49 (m, 1H), 2.77 (m, 1H), 1.56 (s, 6H).

Example 109

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-9-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

16.6 mg (7.6%) of the title compound as an off white solid was isolatedfrom the above described mixture of diastereomers by LC-2D MSchromatography in acidic mode (formic acid) Method 14. LCMS Method/5(ES+) RT 5.95 min., 564 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (d,J=6.8 Hz, 1H), 8.99 (m, 2H), 8.25 (m, 1H), 7.81 (m, 1H), 7.52 (m, 3H),6.42 (m, 1H), 5.23 (m, 1H), 4.99 (m, 1H), 3.53 (d, J=6.7 Hz, 1H), 2.80(m, 1H), 1.56 (s, 6H).

Example 110

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

28.6 mg (13%) of the title compound as an off white solid was isolatedfrom the above described mixture of diastereomers by LC-2D MSchromatography in acidic mode (formic acid) Method 14. LCMS Method/5(ES+) RT 5.96 min., 564 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (m,1H), 8.89 (m, 2H), 8.44 (m, 1H), 7.93 (m, 1H), 7.68 (m, 1H), 7.38 (m,2H), 6.39 (m, 1H), 5.17 (m, 1H), 4.97 (m, 1H), 3.59 (m, 1H), 2.87 (m,1H), 1.55 (s, 6H).

Example 111

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

9.8 mg (5%) of the title compound as an off white solid was isolatedfrom the above described mixture of diastereomers by LC-2D MSchromatography in acidic mode (formic acid) Method 14 . LCMS Method/5(ES+) RT 5.91 min., 564 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.19 (m,1H), 9.10 (m, 1H), 8.25 (m, 1H), 7.67 (m, 1H), 7.49 (m, 4H), 6.32 (s,1H), 5.40 (m, 1H), 4.92 (m, 1H), 3.53 (m, 1H), 2.75 (m, 1H), 1.60 (s,6H)

Example 112

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-3-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

9.8 mg (5%) of the title compound as an off white solid was isolatedfrom the above described mixture of diastereomers by LC-2D MSchromatography in acidic mode (formic acid) Method 14. LCMS Method/5(ES+) RT 6.07 min., 564 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.45 (d,J=6.8 Hz, 1H), 8.98 (m, 2H), 8.52 (m, 1H), 7.88 (m, 2H), 7.70 (m, 1H),7.57 (d, J=6.8 Hz, 1H), 6.42 (m, 1H), 5.17 (m, 1H), 4.97 (m, 1H), 3.52(m, 1H), 2.86 (m, 1H), 1.56 (s, 6H).

Example 113

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanopyrido[1′,2′:1,2]imidazo[4,5-c][1]benzazepin-2-yl]pyrimidin-2-yl}propan-2-ol

To a solution of Intermediate 157 (69 mg, 0.12 mmol) in THF (3 mL) wasadded tetrabutylammonium fluoride (0.25 mL, 0.25 mmol) and reactionstirred at room temperature for 1.5 hours. The reaction mixture wasconcentrated in vacuo and the residue dissolved in EtOAc (30 mL) and theorganic phase washed with water (2×30 mL), brine (30 mL), dried (MgSO₄),filtered and concentrated in vacuo. Crude material was purified bycolumn chromatography (SiO₂, 0-20% MeOH in DCM) and further purified bypreparative HPLC-MS to give the title compound as a yellow solid (2 mg,3.6%) ¹H NMR (300 MHz, Methanol-d4) δ 8.97 (s, 2H), 8.38 (d, J=7.1 Hz,1H), 7.38 (d, J=11.0 Hz, 1H), 6.96 (t,J=74.3 Hz, 1H), 6.88 (t,J=8.2 Hz,1H), 6.33 (dd,J=13.6, 8.3 Hz, 2H), 4.85-4.72 (m, 2H), 2.97-2.88 (m, 1H),2.21 (d,J=10.3 Hz, 1H), 1.66 (s, 6H)

LCMS Method 3 (ES+) 468 (M+H)⁺, RT 1.94 minutes.

LCMS Method 4 (ES+) 468 (M+H)⁺, RT 1.76 minutes.

Example 114

(7R,14R)-1-(difluoromethoxy)-11-[2-(cis-1,3-dihydroxy-3-methylcyclobutyl)pyrimidin-5-yl]-6-trideutero-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of Intermediate 160 (220 mg, 0.34 mmol) in THF (3 mL) wasadded tetrabutylammonium fluoride (1 mL, 1.0M in THF) and the reactionstirred for 18 hours. Reaction mixture was diluted with DCM (25 mL) andwashed with water (3×25 mL), the aqueous was extracted with DCM (3×25mL), combined organics washed with brine and dried (by passage through aphase separator cartridge) and concentrated in vacuo. The crude materialwas purified by column chromatography (SiO₂, gradient elution withDCM/MeOH/0.88 aqueous NH₃: 97.5%:2.25%:0.25% to 87.5%:11.25%:1.25%), togive the title compound (134 mg, 74%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 2H), 8.28 (dd, J=5.6, 3.8 Hz, 1H),7.79 (d, J=8.5 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H), 7.69 (t, J=73.6 Hz, 1H),7.65 (dd, J=8.5, 1.7 Hz, 1H), 7.52-7.48 (m, 2H), 6.32 (d, J=7.1 Hz, 1H),5.62 (s, 1H), 5.26 (d, J=7.2 Hz, 1H), 4.96 (s, 1H), 3.53 (dt, J=14.2,7.3 Hz, 1H), 2.95-2.87 (m, 2H), 2.85 (d, J=13.8 Hz, 1H), 2.42 (d, J=13.2Hz, 2H), 1.09 (s, 3H).

LCMS: Method 3 (ES+) 537 (M+H)⁺, RT 1.53 minutes.

LCMS: Method 4 (ES+) 537 (M+H)⁺, RT 1.54 minutes.

Example 115

Ethyl(7R,14S)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate

To a solution of Intermediate 188 (1.57 g, 2.87 mmol) in THF (30 mL) at0° C. was added potassium bis(trimethylsilyl)amide (4.4 mL, 4.4 mmol)and reaction stirred at 0° C. for 1 hour. The reaction was quenched withwater (50 mL) and extracted with EtOAc (4×100 mL), the combined organicsdried (MgSO₄), filtered and concentrated in vacuo to give an orange oil.Purification by column chromatography (SiO₂, 11-22% EtOAc in DCM) andfreeze drying from acetonitrile/water gave the title compound (607 mg,47%) as an orange solid.

LCMS: Method 3 (ES+) 451 (M+H)⁺, RT 2.51 minutes.

LCMS: Method 4 (ES+) 451 (M+H)⁺, RT 2.49 minutes.

Example 118

Ethyl(7R,14S)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate

The title compound was prepared in accordance with the Method describedfor Example 88 from. Example 115 (200 mg, 0.44 mmol),tris(dibenzylideneacetone)dipalladium(0) (21 mg, 0.022 mmol),tricyclohexylphosphonium tetrafluoroborate (21 mg, 0.055 mmol) and2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (190mg, 0.72 mmol) and K₃PO₄ (282 mg, 1.33 mmol). The crude material waspurified by column chromatography (SiO₂, 0-20% MeOH in DCM) and furtherpurified by preparative HPLC to give Example 118 (3 mg, 1.2%) as a whitesolid.

Example 118-Ethyl(7R,14S)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate

LCMS: Method 3 (ES+) 553 (M+H)⁺, RT 2.18 minutes

LCMS: Method 4 (ES+) 553 (M+H)⁺, RT 2.18 minutes

Example 119

2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-oxido-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from Intermediate 163 (45 mg, 0.1 mmol),tris(dibenzylideneacetone)dipalladium(0) (6 mg, 0.0064 mmol),tricyclohexylphosphonium tetrafluoroborate (6 mg, 0.016 mmol) and2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (43mg, 0.16 mmol), K₃PO₄ (64 mg, 0.30 mmol) dissolved in water (40 μL) and1,4-dioxane (1 mL) by the method of Example 89. The reaction mixture wasdiluted with water (15 mL) and DCM (50 mL), acidified to pH 4 usingacetic acid, layers separated and the aqueous phase extracted with DCM(4×15 mL). The combined organic phases were dried (phase separator) andconcentrated in vacuo. The crude material was then dissolved in DMSO(450 μL) and water (50 μL) and lithium chloride (20 mg, 0.47 mmol) addedand the reaction mixture heated at 130° C. in a sealed microwave vialfor 1.5 hours. The material was purified by preparative HPLC to give thetitle compound (9 mg, 19%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ9.03 (s, 2H), 7.82 (d, J=8.5 Hz, 1H), 7.71-7.65 (m, 1H), 7.65-7.58 (m,2H), 7.57-7.51 (m, 2H), 7.48 (t, J=73.2 Hz, 1H), 6.21 (d, J=8.3 Hz, 1H),5.07 (s, 1H), 4.01 (t, J=6.7 Hz, 1H), 3.96-3.86 (m, 1H), 3.78 (d, J=12.3Hz, 1H), 3.41-3.30 (m, 1H), 2.51 (d, J=1.8 Hz, 1H), 1.51 (s, 6H). LCMS:Method 3 (ES+) 497 (M+H)⁺, RT 1.63 minutes.

LCMS: Method 4 (ES+) 497 (M+H)⁺, RT 1.60 minutes

Example 120

2-{5-[(7R,14R)-1-(difluoromethoxy)-5,5-dioxido-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

The title compound can be prepared from Intermediate 162, and2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester bythe Method of Example 89 to provide, after purification by columnchromatography (SiO₂, 80-100% EtOAc in DCM, followed by 0-10% MeOH inEtOAc), the title compound as a white solid. Note: The ester is observedto decarboxylate during the reaction conditions to provide the desiredproduct. If decarboxylation is not complete it can be further enabled byhydrolysis of the ester to the carboxylic acid followed by acidcatalysed decarboxylation. ¹H NMR (300 MHz, DMSO-d₆) δ 9.05 (s, 2H),7.94 (dd, J=6.6, 2.5 Hz, 1H), 7.72 (q, J=8.5 Hz, 2H), 7.63 (t, J=72 Hz,1H), 7.59 (dd, J=8.4, 1.8 Hz, 1H), 7.51 (d, J=1.2 Hz, 2H), 6.34 (d,J=8.5 Hz, 1H), 5.09 (s, 1H), 4.37 (dd, J=14.6, 2.0 Hz, 1H), 4.18-3.95(m, 2H), 3.56-3.43 (m, 1H), 2.77 (d, J=13.2 Hz, 1H), 1.53 (s, 6H). LCMS:Method 3 (ES+) 513 (M+H)⁺, RT 1.65 minutes. LCMS: Method 4 (ES+) 513(M+H)⁺, RT 1.62 minutes

Example 121

2-{5-[(6R,7R,14S)-1-(difluoromethoxy)-6-(2-hydroxypropan-2-yl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

The title compound was prepared from Intermediate 164 (27 mg, 0.062mmol), tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.0032 mmol),tricyclohexylphosphonium tetrafluoroborate (2.8 mg, 0.007 mmol) and2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (27mg, 0.10 mmol), K₃PO₄ (40 mg, 0.19 mmol) suspended in a mixture of water(40 μL) and 1,4-dioxane (220 μL) in accordance with the method ofExample 89. The reaction mixture was partitioned between DCM (10 mL) andsaturated aqueous sodium bicarbonate solution (10 mL), layers separatedand the aqueous phase extracted with DCM (3×10 mL). The combined organicphases were dried (phase separator) and concentrated in vacuo. The crudematerial was purified by preparative HPLC-MS to give the title compound(2 mg, 6%) as an off-white solid.

¹H NMR (300 MHz, Methanol-d₄) δ 8.96 (s, 2H), 7.80 (d, J=8.5 Hz, 1H),7.56 (dd, J=8.4, 1.7 Hz, 1H), 7.37 (dd, J=8.9, 1.8 Hz, 2H), 7.32-7.22(m, 2H), 7.15 (t, J=73.0 Hz, 1H), 6.40 (d, J=8.3 Hz, 1H), 4.36 (d, J=7.4Hz, 1H), 3.60 (s, 1H), 3.51 (dt, J=12.4, 7.8 Hz, 1H), 3.32 (m, 1H), 2.32(d, J=12.9 Hz, 1H), 1.62 (s, 6H), 1.52 (s, 3H), 1.50 (s, 3H).

LCMS: Method 3 (ES+) 539 (M+H)⁺, RT 2.07 minutes.

LCMS: Method 4 (ES+) 539 (M+H)⁺, RT 1.99 minutes.

Example 122

2-{5-[(6S,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-olExample 123

2-{5-[(6R,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

Intermediate 165 (30 mg, 0.07 mmol),2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (33mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium(0) (4 mg, 0.01mmol), tricyclohexylphosphonium tetrafluoroborate (4 mg, 0.01 mmol) and1,4-dioxane (0.25 mL) were added to a microwave tube, degassed, thenK₃PO₄ (50 mg, 0.23 mmol) dissolved in water (40 μL) was added themixture deagassed and then heated at 130° C. under nitrogen in themicrowave for 2 hours. The reaction mixture was partitioned betweenwater (10 mL) and DCM (10 mL), the layers separated and the aqueousphase extracted with DCM (3×10 mL). The combined organics phases weredried (phase separator) and concentrated in vacuo. Purification bycolumn chromatography (SiO₂, 50-100% EtOAc in hexane, followed by 0-20%MeOH in EtOAc) gave Example 122 (7 mg, 19%) as a white solid and Example123 (3 mg, 8%) as a white solid.

Example 122:2-{5-[6S,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

¹H NMR (300 MHz, DMSO-d₆) δ 9.00 (s, 2H), 7.77 (d, J=8.4 Hz, 1H), 7.58(dd, J=8.4, 1.8 Hz, 1H), 7.50 (t, J=73.6 Hz, 1H), 7.40 (d, J=1.3 Hz,1H), 7.27-7.19 (m, 3H), 6.23 (d, J=8.5 Hz, 1H), 5.29-5.22 (m, 1H), 5.07(s, 1H), 4.01 (dd, J=7.6, 4.6 Hz, 1H), 3.81 (d, J=5.3 Hz, 1H), 3.66-3.54(m, 1H), 3.45 (dt, J=9.7, 5.4 Hz, 1H), 3.26-3.13 (m, 1H), 2.53 (d, J=9.6Hz, 1H), 1.52 (s, 6H).

LCMS: Method 3 (ES+) 511 (M+H)⁺, RT 1.81 minutes.

LCMS: Method 4 (ES+) 511 (M+H)⁺, RT 1.75 minutes.

Example 123:2-{5-[(6R,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

¹H NMR (300 MHz, DMSO-d₆) δ 8.99 (s, 2H), 7.77 (d, J=8.4 Hz, 1H), 7.57(dd, J=8.4, 1.8 Hz, 1H), 7.50 (t, J=73.5 Hz, 1H) 7.38 (s, 1H), 7.26 (d,J=4.2 Hz, 3H), 6.26 (d, J=8.5 Hz, 1H), 5.34 (s, 1H), 5.07 (s, 1H), 4.01(d, J=6.5 Hz, 1H), 3.95-3.86 (m, 1H), 3.87-3.71 (m, 1H), 3.66-3.51 (m,1H), 3.53-3.39 (m, 1H), 2.35 (d, J=13.2 Hz, 1H), 1.52 (s, 6H).

LCMS: Method 3 (ES+) 511 (M+H)⁺, RT 1.84 minutes.

LCMS: Method 4 (ES+) 511 (M+H)⁺, RT 1.77 minutes.

Example 124

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 166 (750 mg, 1.37 mmol) was dissolved in anhydroustetrahydrofuran (20 mL) and cooled to -78° C. under nitrogen. Potassiumbis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 mol/L) was added dropwise at −78° C. and stirred for 30 minutes before the addition ofiodotrideuteromethane (0.13 mL, 2.1 mmol). The reaction mixture wasstirred for 2 hours with warming to room temperature. 2M HC1(aq) (10 mL)was added and the mixture stirred for 2 hours to remove thetrimethylsilyl protecting group. The mixture was treated with 2M NaOH(15 mL) and extracted with EtOAc (50 mL). The organic layer was dried(sodium sulfate), filtered and concentrated in vacuo. Purification bychromatography (silica, 0 to 10% MeOH in dichloromethane) gave the titlecompound as a white solid after drying under vacuum (500 mg, 74% yield).¹H NMR (300 MHz, DMSO-d₆) δ 8.74 (dd, J=2.4, 0.8 Hz, 1H), 8.34-8.20 (m,1H), 7.99 (dd, J=8.3, 2.4 Hz, 1H), 7.80-7.68 (m, 3H), 7.67 (t, 1H,J_(H-F) 75 Hz), 7.60-7.46 (m, 3H), 6.29 (d, J=7.0 Hz, 1H), 5.24 (d,J=6.9 Hz, 2H), 3.52 (dt, J=14.1, 7.2 Hz, 1H), 2.83 (d, J=13.8 Hz, 1H),1.48 (s, 6H). LC/MS Method 3: RT 1.77 minutes, m/z 494.

Example 125

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)-1-oxidopyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 166 (240 mg, 0.437 mmol) was dissolved in THF (20 mL) and 2mL of 2M aqueous HCl added and the mixture was stirred at roomtemperature for 30 minutes. LCMS shows complete removal of TMS group.The mixture was partitioned between DCM and saturated aqueous sodiumcarbonate solution and concentrated in vacuo. The residue wasredissolved in DCM (10 mL) and mCPBA (103 mg, 0.46 mmol) was added andthe mixture stirred for 2 hours. The reaction was washed with 2M sodiumhydroxide (10 mL) and the organic layer concentrated in vacuo. Theresidual solid was purified by chromatography (silica 10 g, 0 to 15%MeOH in DCM gradient) to give the title compound as an off-white solid,(100 mg, 46% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (d, J=6.8 Hz, 1H),8.54 (t, J=1.1 Hz, 1H), 8.23 (dd, J=6.1, 3.3 Hz, 1H), 7.77-7.68 (m, 4H),7.66 (t, 1H, J_(H-F) 73.5 Hz) 7.56-7.45 (m, 2H), 7.00 (s, 1H), 6.36 (d,J=7.1 Hz, 1H), 4.89 (m, 1H) 3.49 (dt, J=13.7, 7.0 Hz, 1H), 2.75 (d,J=13.3 Hz, 1H), 1.61 (s, 6H). LC/MS Method 3: RT 1.57 minutes, m/z 493.

Example 126

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)-1-oxidopyridin-3-yl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 124 (276 mg, 0.56 mmol) was dissolved in dichloromethane (15 mL)and 3-chloroperoxybenzoic acid (1.05 equiv., 0.59 mmol, 77%) was addedand the mixture was stirred for 18 hours at room temperature. Themixture was then diluted with dichloromethane (50 mL), washed withsaturated aqueous sodium bicarbonate solution (50 mL), and concentratedin vacuo. The residue was purified by chromatography (silica, 0 to 15%methanol gradient in dichloromethane). The product fractions wereconcentrated in vacuo and the residues freeze dried fromacetonitrile/water to give the title compound as a white solid, (165 mg,58% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (t, J=1.1 Hz, 1H),8.34-8.18 (m, 1H), 7.97-7.34 (m, 8H), 6.99 (s, 1H), 6.30 (d,J=7.1 Hz,1H), 5.25 (d, J=7.1 Hz, 1H), 3.52 (dt, J=14.2, 7.3 Hz, 1H), 2.83(d,J=13.8 Hz, 1H), 1.61 (s, 6H). LC/MS Method 3: RT 1.67 minutes, m/z510.

Example 127

2-{5-[(6R,12R)-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-amine,dihydrochloride salt

Intermediate 114 (300 mg, 0.95 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.05 equiv., 0.0474 mmol), potassium acetate (4equiv., 3.80 mmol) and bis(pinacolato)diboron (292 mg, 1.14 mmol) weredissolved in dry dioxane (10 ml) and the mixture heated to reflux for 2hours. The mixture was partitioned between dichloromethane and water andthe organic layer was concentrated in vacuo to give the crude boronate.The intermediate was dissolved in 1,4-dioxane (2.5 ml) and added to amicrowave tube containing Example 88 (300 mg, 0.822 mmol),tris(dibenzylideneacetone)-dipalladium(0) (39 mg, 0.041 mmol),tricyclohexylphosphonium tetrafluoroborate (38 mg, 0.1 mmol) and asolution of potassium phosphate (523 mg, 2.47 mmol) in water (0.5 ml).The mixture was degassed and refilled with nitrogen twice then heated to140° C. in the microwave for 2 hours. After cooling the mixture waspartitioned between dichloromethane (50 mL) and water (50 mL) and theorganic layer dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by chromatography (silica, 0 to 100% EtOAc gradientin DCM) to give the BOC protected amine of the title compound as a palebrown solid. The solid was dissolved in 1,4-dioxane (2 mL) and 4.0M HClin 1,4-dioxane (10 mL) added and the mixture stirred for 2 hours. Thesolvent was removed in vacuo and the residue partitioned between DCM andwater. The aqueous layer was washed with DCM (5 mL) and the aqueousphase was freeze dried to give the title compound as an off-white solid,(330 mg,75% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.20 (s, 2H), 8.89-8.54(br m, 3H, R—NH3⁺), 7.95-7.66 (m, 3H), 7.58 (dt, J_(H-F)=75 Hz, 1.8 Hz,1H), 7.39-7.21 (m, 1H), 6.98 (dd, J=8.1, 2.6 Hz, 2H), 6.14 (d, J=5.2 Hz,1H), 5.11 (d, J=5.0 Hz, 1H), 3.55-3.43 (m, 1H), 2.73 (d, J=12.3 Hz, 1H),1.71 (s, 6H). LC/MS Method 3: RT 1.62 minutes, m/z 466.

Example 128

tert-Butyl3-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}-3-hydroxypyrrolidine-1-carboxylate

To a mixture of Intermediate 159 (200 mg, 0.41 mmol),tris(dibenzylideneacetone) dipalladium(0) (19 mg, 0.021 mmol),tricyclohexylphosphonium tetrafluoroborate (16 mg, 0.041 mmol) andIntermediate 167 (170 mg, 0.50 mmol) in 1,4-dioxane (1.5 mL) was added asolution of potassium phosphate tribasic (271 mg, 1.24 mmol) in water(0.15 mL). The reaction mixture was heated at 110° C. in the microwavefor 3 hours. cooled, partitioned between EtOAc (100 mL) and water (100mL) and the organic layer dried (sodium sulphate), filtered andconcentrated in vacuo. The residue was purified by chromatography(silica, 100% EtOAc then to 7% MeOH in EtOAc gradient) to give the titlecompound as a white solid (128 mg, 50% yield). ¹H NMR (300 MHz, DMSO-d₆)δ 8.79 (s, 1H), 8.27 (dd, J=5.8, 3.6 Hz, 1H), 8.05 (dd, J=8.2, 2.4 Hz,1H), 7.85-7.68 (m, 3H), 7.67 (t, J_(H-F)=73.4 Hz, 1H), 7.60-7.45 (m,3H), 6.30 (d, J=7.0 Hz, 1H), 5.71 (s, 1H), 5.24 (d, J=7.1 Hz, 1H), 3.72(t, J=10.6 Hz, 1H), 3.64-3.38 (m, 2H), 2.83 (d, J=13.7 Hz, 1H), 1.76 (s,2H), 1.40 (9H, s), 1.33-1.06 (m, 2H). LC/MS Method 3: RT 2.18 minutes,m/z 621.

Example 129

(7R,14R)-1-(difluoromethoxy)-11-[6-(3-hydroxypyrrolidin-3-yl)pyridin-3-yl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one,dihydrochloride salt

Example 128 (120 mg, 0.193 mmol) was dissolved in 1,4-dioxane (5 mL) and4M HCl in 1,4-dioxane (5 mL) added and the mixture stirred at roomtemperature for 1 hour. After removing the solvent in vacuo the residuewas treated with diethyl ether (5 mL) and isohexanes (5 mL). Theresultant solid was filtered off, washed with diethyl ether (10 mL) anddried under high vacuum for 1 hour to give the title compound as anoff-white solid (88 mg, 72%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.56 (s, 1H),9.41 (s, 1H), 8.88-8.76 (m, 1H), 8.28 (dd, J=6.0, 3.4 Hz, 1H), 8.21-8.04(m, 1H), 7.98-7.32 (m, 4H), 7.68 (t, J_(H-F)=73.5 Hz, 1H) 6.34 (d, J=7.0Hz, 1H), 5.31 (d, J=7.1 Hz, 1H), 3.76-3.27 (m, 4H), 2.87 (d, J=13.8 Hz,1H), 2.40 (t, J=11.1 Hz, 1H), 2.28-2.22 (m, 1H), 1.89-1.83 (m, 1H).LC/MS Method 3: RT 1.32 minutes, m/z 521.

Example 130

Methyl(2-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

Intermediate 168 (226 mg, 0.826 mmol) and Intermediate 159 (200 mg,0.4130 mmol) were coupled in accordance with the method of Example 128.Purification by chromatography (silica, 0 to 10% MeOH in DCM) and freezedrying of the residue gave the title compound as a white solid (197 mg,87% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.01 (s, 2H), 8.37-8.19 (m, 1H),7.81-7.71 (m, 2H), 7.68 (dd, Jx_F =72.6, 73.8 Hz, 1H), 7.62 (dd, J=8.5,1.8 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J=4.9 Hz, 2H), 6.31 (d, J=7.1 Hz,1H), 5.25 (d, J=7.1 Hz, 1H), 3.56-3.47 (m, 1H), 3.44 (s, 3H), 2.84 (d,J=13.8 Hz, 1H), 1.61 (s, 6H). LC/MS Method 3: RT 1.95 minutes, m/z 552.

Example 131

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)-4-methylpyrimidin-5-yl]-6-trideutero-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was synthesised from Intermediate 110 (400 mg, 1.018mmol) and Intermediate 62 (1.2 equivalents) in accordance with theMethod described for Example 128. Purification by column chromatography(silica, DCM/EtOAc gradient) gave the desired product as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.28 (dt, J=8.3, 4.2 Hz, 1H),7.86-7.24 (m, 6H), 6.27 (d, J=7.1 Hz, 1H), 5.25 (d, J=7.1 Hz, 1H), 5.06(s, 1H), 3.61-3.40 (m, 1H), 2.83 (d, J=13.8 Hz, 1H), 2.45 (s, 3H), 1.53(s, 6H). LC/MS: Method 3 ESI MH⁺ 509, retention time 1.85 minutes.

Example 132

(7R,14R)-11-chloro-1-(difluoromethoxy)-5-methylidene-5,14-dihydro-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazoeine

Intermediate 169 (37.0 mg, 0.08 mmol) was dissolved in THF (2 mL), andsodium hydride (20.0 mg, 0.83 mmol) was added at 0° C. and the mixturewas stirred for 1 hour. Water was added to quench the reaction and themixture was partitioned between water and DCM (2×10 mL). The organicswere combined, dried (MgSO₄), filtered and concentrated in vacuo. Thecrude product was purified by preparative HPLC-MS to give theO-alkylated product (3.5 mg, 12%).

¹H NMR (300 MHz, DMSO-d₆) δ 7.78-7.65 (m, 2H), 7.53-7.14 (m, 5H), 6.19(d, J=7.1 Hz, 1H), 5.68 (d, J=4.1 Hz, 1H), 4.73 (dd, J=13.8, 0.9 Hz,2H), 3.27-3.13 (m, 1H), 2.79 (d, J=13.7 Hz, 1H). LC/MS: Method 3 ESI MH⁺375, retention time 2.36 minutes.

Example 133

(7R,14R)-1-(difluoromethoxy)-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyrimidin-5-yl}-6-trideutero-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

A mixture of Intermediate 133 (600 mg, 0.84 mmol), Intermediate 110 (314mg, 0.80 mmol), K₃PO₄ (594 mg, 2.80 mmol), tricyclohexylphosphoniumtetrafluoroborate (37 mg, 0.1 mmol) andtris(dibenzylideneacetone)dipalladium(0) (90 mg, 0.1 mmol) weresuspended in a mixture of 1,4-dioxane (5 mL) and water (0.4 mL). Themixture was degassed and purged with N₂ before heating in a microwave at140° C. for 2 hours. The reaction mixture was quenched with water andextracted with EtOAc (3×10 mL). The combined organic phases were driedwith Na₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by column chromatography (0-10% MeOH in DCM) to give the titlecompound (200 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (dd, J=7.5, 2.0Hz, 1H), 8.21 (s, 1H), 7.80-7.31 (m, 6H), 7.20 (dd, J=8.4, 1.7 Hz, 1H),6.25 (d, J=7.1 Hz, 1H), 5.24 (d, J=7.1 Hz, 1H), 4.31 (d, J=10.1 Hz, 2H),4.09 (d, J=10.1 Hz, 2H), 3.52 (dt, J=14.1, 7.3 Hz, 1H), 2.82 (d, J=13.7Hz, 1H), 2.29 (s, 3H). LC/MS: Method 3 ESI MH⁺ 590, retention time 1.97minutes.

Example 134

(7R,14R)-1-(difluoromethoxy)-11-[6-(piperazin-1-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

A mixture of1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine(277 mg, 0.96 mmol), Example 11 (300 mg, 0.79 mmol), K₃PO₄ (600 mg, 2.83mmol), tricyclohexylphosphonium tetrafluoroborate (37 mg, 0.1 mmol) weresuspended in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL). Themixture was degassed and purged with N₂ before the addition oftris(dibenzylideneacetone) dipalladium(0) (75 mg, 0.08 mmol). Themixture was degassed for 10 minutes before heating in a microwave at105° C. for 1 hour. The reaction mixture was quenched with water andextracted with EtOAc (3×10 mL). The aqueous phase was basified withsaturated aqueous NaHCO₃ solution and extracted with DCM (3×10 mL). Theorganics were combined, dried with Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by column chromatography (0-30%MeOH in DCM) to give the title compound (57 mg, 14%). The HCl salt wasprepared by addition of 2 equivalents of HCl followed by freeze-drying.¹H NMR (300 MHz, Deuterium Oxide) δ 8.13 (dd, J=7.2, 2.3 Hz, 1H), 8.06(d, J=2.3 Hz, 1H), 7.85 (dd, J=9.2, 2.4 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H),7.48-7.27 (m, 3H), 7.00 (d, J=9.4 Hz, 2H), 6.54 (d, J=7.1 Hz, 1H), 5.17(d, J=6.6 Hz, 1H), 3.82 (t, J=5.4 Hz, 4H), 3.56-3.34 (m, 5H), 2.90 (d,J=13.8 Hz, 1H). LC/MS: Method 3 ESI MH⁺ 503, retention time 1.41minutes.

Example 135

(7R,14R)-1-(difluoromethoxy)-6-trideutero-methyl-11-[6-(piperazin-1-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

A mixture of1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine(277 mg, 0.96 mmol), Intermediate 110 (300 mg, 0.80 mmol), K₃PO₄ (600mg, 2.83 mmol), tricyclohexylphosphonium tetrafluoroborate (37.0 mg, 0.1mmol) were suspended in a mixture of 1,4-dioxane (3 mL) and water (0.3mL). The mixture was degassed and purged with N₂ before the addition oftris(dibenzylideneacetone) dipalladium(0) (75 mg, 0.08 mmol). Themixture was degassed for 10 min before heating in a microwave at 105° C.for 1 hour. The reaction mixture was quenched with saturated aqueousNaHCO₃ solution and extracted with EtOAc (3×10 mL). The combined organicphases were acidified with aqueous HCl (2N), extracted with water (3×10mL), and the aqueous phase neutralised with NaOH solution (10%) andextracted with DCM (3×10 mL). The organics were combined, dried (MgSO₄),filtered and concentrated in vacuo to give the title compound (170 mg,43%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.38 (d, J=2.6 Hz, 1H), 8.33-8.22 (m,1H), 7.94-7.36 (m, 7H), 6.88 (d, J=8.7 Hz, 1H), 6.27 (d, J=7.0 Hz, 1H),5.21 (d, J=7.1 Hz, 1H), 3.60-3.39 (m, 5H), 2.88-2.68 (m, 5H). LC/MS:Method 3 ESI MH⁺ 520, retention time 1.45 minutes.

Example 136

(7R,14R)-1-(difluoromethoxy)-6-trideutero-methyl-11-{6-[4-(methylsulfonyl)piperazin-1yl]pyridine-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-oneExample 135 (80 mg, 0.15 mmol) was dissolved in DCM (5 mL) andN,N-diisopropylethylamine (55 μL, 0.31 mmol) was added to the mixture at0° C. The mixture was stirred for 5 minutes before the addition ofmethanesulfonyl chloride (18 uL, 0.23 mmol). The mixture was stirred at0° C. for 1 hour before the completion of the reaction. The mixture wasquenched with saturated NH₄Cl solution and extracted with DCM (3×10 mL).The organic phases were combined, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by preparativeHPLC-MS to give the title compound (30 mg, 32%). ¹H NMR (300 MHz,DMSO-d₆) δ 8.42 (d, J=2.5 Hz, 1H), 8.27 (dd, J=6.0, 3.5 Hz, 1H),7.97-7.39 (m, 7H), 7.01 (d, J=8.9 Hz, 1H), 6.27 (d, J=7.0 Hz, 1H), 5.22(d, J=7.1 Hz, 1H), 3.69 (t, J=5.1 Hz, 4H), 3.50 (dt, J=14.2, 7.3 Hz,1H), 3.21 (t, J=5.1 Hz, 4H), 2.91 (s, 3H), 2.81 (d, J=13.8 Hz, 1H).LC/MS: Method 3 ESI MH⁺ 598, retention time 1.95 minutes.

Example 137

(7R,14R)-1-(difluoromethoxy)-11-{2-[2-(dimethylamino)propan-2-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

A solution of Intermediate 171 (175 mg, 0.37 mmol) in 1,4-dioxane (2 mL)was added to a mixture of Intermediate 170 (120 mg, 0.49 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethanecomplex (16.0 mg, 0.0196 mmol), potassium phosphate tribasic (240 mg,1.11 mmol) in 1,4-dioxane (2 mL) and water (0.3 mL). The mixture wasdegassed and purged with N₂ before heating at 110° C. for 2 hours. Thereaction mixture was quenched with saturated aqueous NaHCO₃ solution andextracted with EtOAc (3×10 mL). The organics were combined, dried withNa₂SO₄, filtered and concentrated in vacuo. The crude product purifiedby column chromatography (0-40% MeOH in DCM (1% Et3N)) to give the titlecompound (18 mg, 9%). ¹H NMR (300 MHz, DMSO-d6) δ 9.16 (d, J=6.9 Hz,1H), 9.05 (s, 2H), 8.23 (dd, J=6.3, 3.1 Hz, 1H), 8.03-7.37 (m, 6H), 6.37(d, J=7.0 Hz, 1H), 4.90 (t, J=6.7 Hz, 1H), 3.59-3.39 (m, 1H), 2.75 (d,J=13.5 Hz, 1H), 2.13 (s, 6H), 1.51 (s, 6H). LC/MS: Method 3 ESI MH⁺ 505,retention time 1.44 minutes.

Example 138

(7R,14R)-1-(difluoromethoxy)-11-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

A mixture of [2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]boronic acid (310mg, 1.40 mmol), Example 11 (350 mg, 0.93 mmol), K₃PO₄ (592 mg, 2.80mmol), tricyclohexylphosphonium tetrafluoroborate (36 mg, 0.1 mmol) andtris(dibenzylideneacetone) dipalladium(0) (85 mg, 0.1 mmol) weresuspended in a mixture of 1,4-dioxane (10 mL) and water (0.5 mL). Themixture was degassed and purged with N₂ before heating in an oil bath at105° C. for 16 hours. The reaction mixture was quenched with water andextracted with EtOAc (3×10 mL), and the combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Purification by columnchromatography (0%-10% MeOH in DCM) afforded the title compound (130 mg,27%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (d, J=6.8 Hz, 1H), 8.69 (s, 2H),8.29-8.16 (m, 1H), 8.11 (s, 1H), 7.74-7.63 (m, 2H), 7.60 (dd, J=1.8, 0.7Hz, 1H), 7.55-7.39 (m, 3H), 6.33 (d, J=7.0 Hz, 1H), 4.87 (t, J=6.7 Hz,2H), 4.23 (s, 2H), 3.96 (t, J=5.4 Hz, 2H), 3.47 (dt, J=13.5, 6.9 Hz,2H), 2.73 (d, J=13.3 Hz, 1H).LC/MS: Method 3 ESI MH⁺ 518, retention time1.54 minutes.

Example 139

1-[(6R,12R)-11-(difluoromethoxy)-2-(1-methyl-1H-pyrazol-4-yl)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]-2-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)ethanone

The title compound was prepared from1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and Preparative Example 40 in accordance with the Method described forExample 20 to give, following purification by preparative HPLC a whitesolid (2 mg, 4% yield). LC/MS: Method 3 RT 1.72 mins, [M+H]⁺=563. ¹H NMR(300 MHz, Methanol-d4) δ 8.19 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.81 (s,1H), 7.70-7.55 (m, 2H), 7.49-7.42 (m, 1H), 7.25 (t, J=8.5 Hz, 1H), 7.13(t, J=73.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.35 (d, J=4.0 Hz, 1H), 6.14(d, J=4.4 Hz, 1H), 4.37 (s, 2H), 4.24 (d, J=11.6 Hz, 2H), 4.11 (d,J=11.5 Hz, 2H), 3.95 (s, 3H), 3.86 (dd, J=11.5, 6.7 Hz, 4H), 3.29-3.20(m, 1H), 2.76-2.62 (m, 3H).

Example 140

(6R,12R)-2-chloro-11-(difluoromethoxy)-7-[(6-methoxypyridin-3-yl)sulfonyl]-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

To Intermediate 172 (630 mg, 1.050 mmol) was added anhydrous cesiumacetate (2000 mg, 10.41 mmol), cuprous iodide (510 mg, 2.62 mmol) anddimethyl sulfoxide (1.0 mL). The mixture was sealed and purged 3 timeswith nitrogen. The reaction mixture was stirred for 45 minutes at 160°C. The reaction mixture was cooled at room temperature the solid wasfiltered and the filtrate was evaporated under vacuum. The crudematerial was purified by column chromatography over silica gel usinghexane/ethyl acetate (0 to 100%) as eluent, yielding 133 mg (25% yield)of the title compound as a brown solid. LCMS Method 3: RT 2.07 min,[M+H]⁺=519. δ ¹H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J=2.5 Hz, 1H), 8.39(dd, J=8.9, 2.7 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.49-7.41 (m, 2H), 7.40(t, J=73.3 Hz, 1H). 7.27 (t, J=8.5 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H).6.99-6.92 (m, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.28 (d, J=3.7 Hz, 1H), 6.04(d, J=4.5 Hz, 1H), 3.89 (s, 3H), 3.23-3.13 (m, 1H), 2.54 (d, J=11.9 Hz,1H).

Example 141

5-{[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]sulfonyl}pyridin-2(1H)-one

To a solution of Example 140 (120 mg, 0.23 mmol) in acetonitrile (3.4mL) was added chloromethyltrimethylsilane (0.15 mL, 1.2 mmol) inacetonitrile (3.4 mL) and potassium iodide (195 mg, 1.17 mmol) and thereaction mixture heated at 80° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure, the residue diluted with EtOAc,washed with water and Na₂S₂O₃ 10% aq. solution. The combined organiclayers were washed with brine and filtered through a phase separator andevaporated under vacuum. The crude material was purified by columnchromatography over silica gel using hexane/ethyl acetate (0 to 100%) aseluent, yielding 106 mg (91% yield) of the title compound as a palebrown solid. LCMS Method 3: RT 2.06 min, [M−H]⁺=503/505. ¹H NMR (300MHz, DMSO-d₆) δ 1H NMR (400 MHz, DMSO-d₆) δ 1H NMR (300 MHz, DMSO-d6) δ12.46 (s, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.72-7.62 (m, 1H), 7.50-7.37(m, 2H), 7.41 (t, J=73.3 Hz, 1H), 7.33-7.13 (m, 2H), 6.89 (d, J=8.0 Hz,1H), 6.28 (d, J=9.7 Hz, 1H), 6.16 (d, J=3.7 Hz, 1H), 6.03 (d, J=4.3 Hz,1H), 3.17 (d, J=12.4 Hz, 1H), 2.56 (d, J=12.4 Hz, 1H).

Example 142

2-{5-[(7R,14R)-1-(difluoromethoxy)-5,5-dioxido-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,2,5]benzothiadiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

To a solution of Intermediate 175 (10 mg, 0.024 mmol) in 1,4-dioxane(0.1 mL),2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(9.6 mg, 0.036 mmol), potassium phosphate, (13 mg, 0.061 mmol),tris(dibenzylideneacetone)dipalladium (0) (1.2 mg, 0.0013 mmol),tricyclohexylphosphonium trifluoroborate (1.1 mg, 0.003 mmol) and water(10 μL) were added. The reaction mixture was de-gassed and stirred at140° C. for 5 hours in the microwave. The reaction mixture was filteredthrough a pad of Celite and the residue washed successively with EtOAc,and 20% MeOH in DCM. The filtrate was evaporated under vacuum and thecrude material was purified by preparative HPLC-MS (pH 10) yielding 1.2mg (16% yield) of the title compound as a white solid. LCMS Method 3: RT1.42 min, [M−H]⁺=514. ¹H NMR (400 MHz, Methanol-d4) δ 9.03 (s, 2H), 7.89(dd, J=6.9, 2.2 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H),7.67-7.55 (m, 3H), 7.30 (t, J=72.8 Hz, 1H), 6.60 (d, J=7.8 Hz, 1H), 5.02(d, J=4.9 Hz, 1H), 3.44 (ddd, J=13.2, 7.8, 5.0 Hz, 1H), 3.07 (d, J=13.6Hz, 1H), 1.64 (s, 6H). (OH and NH signals are missing).

Example 143

(7R,14R)-1-(difluoromethoxy)-11-[2-methyl-4-(methylsulfanyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of 4-bromo-3-methylthioanisole (500 mg, 2.23 mmol), in1,4-dioxane (8 mL), bis(pinacolato)diboron (1.2 g, 4.46 mmol) potassiumacetate (885 mg, 8.92 mmol),,1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethanecomplex(92 mg, 0.11 mmol) were added and the solution was degassed and heatedat 100° C., using a preheated oil bath, for 1 hour. The reaction wasquenched by the addition of water and the mixture extracted with EtOAc(x3). The combined organic layers were filtered through a phaseseparator and the solvent was evaporated to give 590 mg (99%) of4,4,5,5-tetramethyl-2-(2-methyl-4-methylsulfanyl-phenyl)-1,3,2-dioxaborolanewhich was used in the next step without further purification. LCMS (ES+)Method 3: 265 (M+H)⁺, RT 1.70 minutes.

To a solution of4,4,5,5-tetramethyl-2-(2-methyl-4-methylsulfanyl-phenyl)-1,3,2-dioxaborolane(590 mg, 2.23 mmol) in 1,4-dioxane (3.8 mL) were added Example 11 (400mg, 1.06 mmol), potassium phosphate (567 mg, 2.67 mmol),tricyclohexylphosphonium tetrafluoroborate (52 mg, 0.138 mmol) andtris(dibenzylideneacetone)dipalladium (0) (108 mg, 0.114 mmol). Thereaction mixture was degassed for 10 mins before heating to 140° C.degree in a microwave for 2 hours. The reaction was quenched with waterand extracted with EtOAc (x3). The combined organic layers were filteredthrough a phase separator and the solvent was evaporated to give a cruderesidue. Purification by column chromatography on silica eluting withEtOAc: MeOH (0 to 20%) gave the title compound (80 mg) as a white solid.LCMS (ES+) Method 3: 478 (M+H)⁺, RT 2.42 minutes. ¹H NMR (300 MHz,DMSO-d6) δ 9.14 (d, J=6.8 Hz, 1H), 8.24 (dd, J=5.8, 3.6 Hz, 1H), 7.63(dd, J=8.4, 0.7 Hz, 1H), 7.55-7.49 (m, 2H), 7.48 (t, J=83.2 Hz, 1H).7.37(dd, J=1.7, 0.7 Hz, 1H), 7.23-7.08 (m, 4H), 6.29 (d, J=7.0 Hz, 1H), 4.87(t, J=6.7 Hz, 1H), 3.48 (dt, J=13.5, 7.0 Hz, 1H), 2.72 (d, J=13.3 Hz,1H), 2.5 (s, 3H), 2.19 (d, J=0.6 Hz, 3H).

Example 144

(7R,14R)-1-(difluoromethoxy)-11-[2-(morpholin-4-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Example 11 (450 mg, 1.20 mmol) and2-morpholinopyrimidin-5-yl)boronic acid (380 mg, 1.82 mmol) inaccordance with the Method described for Example 20 to give, followingpurification by column chromatography over silica gel using hexane/ethylacetate (0 to 100%) then DCM:MeOH (0 to 20%) as eluent, the titlecompound (300 mg, 50% yield) as a pale yellow solid. LCMS (ES+) Method3: 505 (M+H)⁺, RT 1.89 minutes. ¹H NMR (300 MHz, DMSO-d6) δ 9.12 (d,J=6.7 Hz, 1H), 8.66 (s, 2H), 8.22 (t, J=4.7 Hz, 1H), 7.68 (d, J=2.7 Hz,1H), 7.65 (t, J=79.0 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.54-7.40 (m, 3H),6.33 (d, J=7.1 Hz, 1H), 4.87 (t, J=6.7 Hz, 1H), 3.80-3.65 (m, 8H),3.58-3.39 (m, 1H), 2.73 (d, J=13.3 Hz, 1H).

Example 145

(6R,12R)-2-chloro-11-(difluoromethoxy)-7-(pyrimidin-2-yl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

To Intermediate 176 (200 mg, 0.39 mmol) was added cesium acetateanhydrous (600 mg, 3.12 mmol), cuprous iodide (192 mg, 1.0 mmol) anddimethyl sulfoxide (0.4 mL). The mixture was sealed and purged 3 timeswith nitrogen. The reaction mixture was stirred for 45 minutes at 160°C. The reaction mixture was cooled to room temperature the solid wasfiltered and the filtrate was evaporated under vacuum. The crudematerial was purified by column chromatography over silica gel usinghexane/ethyl acetate (0 to 100%) as eluent, followed by a secondpurification by preparative HPLC, yielding 2 mg (1% yield) of the titlecompound as a white solid. LCMS Method 3: RT 2.37 min, [M+H]⁺=426. ¹HNMR (300 MHz, DMSO-d6) δ 8.71 (d, J=4.8 Hz, 2H), 8.00 (d, J=8.7 Hz, 1H),7.59-7.43 (m, 2H), 7.42 (t, J=73.7 Hz, 1H), 7.28-7.11 (m, 3H), 6.82 (d,J=8.3 Hz, 1H), 6.66 (s, 1H), 6.08 (d, J=4.3 Hz, 1H), 3.17 (d, J=11.9 Hz,1H), 2.60 (d, J=12.0 Hz, 1H).

Example 146

Ethyl-(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine-7(12H)-carboxylate

To Intermediate 177 (260 mg, 0.52 mmol) was added sodium acetate (167mg, 2.04 mmol), cuprous iodide (101 mg, 0.52 mmol) and dimethylsulfoxide (6.4 mL). The mixture was sealed and purged 3 times withnitrogen. The reaction mixture was stirred overnight at 100° C.Additional sodium acetate (167 mg, 2.03 mmol) and cuprous iodide (101mg, 0.52 mmol) were added and the reaction was stirred at 160° C. for 1hour. The reaction mixture was cooled to room temperature, the solid wasfiltered and the filtrate was evaporated under vacuum. The crudematerial was purified by column chromatography over silica gel usinghexane/ethyl acetate (0 to 100%) as eluent, followed by a secondpurification by preparative HPLC, yielding 12 mg (6% yield) of the titlecompound as a white solid. LCMS Method 3: RT 2.47 min, [M+H]⁺=420/422.¹H NMR (300 MHz, DMSO-d6) δ 8.02 (d, J=8.6 Hz, 1H), 7.63 (d, J=8.6 Hz,1H), 7.45 (d, J=2.0 Hz, 1H), 7.42 (t, J=73.5 Hz, 1H), 7.29 (t, J=8.5 Hz,1H), 7.19 (dd, J=8.7, 2.1 Hz, 1H), 6.90 (dd, J=8.4, 1.0 Hz, 1H), 6.04(m, 2H), 4.38-4.23 (m, 2H), 3.10 (dt, J=12.1, 4.4 Hz, 1H), 2.56 (d,J=12.1 Hz, 1H), 1.38 (t, J=7.1 Hz, 3H).

Example 147

Ethyl-(6R,12R)-11-(difluoromethoxy)-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine-7(12H)-carboxylate

The title compound was prepared from 2-(1-hydroxy-1-methtylethyl)pyrimidine-5-boronic acid pinacol ester, and Example 146 in accordancewith the Method for Example 20 to give, following purification bypreparative HPLC a white solid (1.2 mg, 8% yield). LC/MS Method 3: RT2.18 mins, [M+H]⁺=522

¹H NMR (300 MHz, Methanol-d4) δ 9.05 (s, 2H), 8.17 (d, J=8.7 Hz, 1H),7.87-7.73 (m, 2H), 7.58 (dd, J=8.5, 1.7 Hz, 1H), 7.25 (t, J=8.5 Hz, 1H),7.14 (t, J=73.3 Hz, 1H), 6.93-6.84 (m, 1H), 6.20 (d, J=4.3 Hz, 2H), 4.43(m, 2H), 3.20 (dt, J=12.1, 4.4 Hz, 1H), 2.65 (d, J=12.0 Hz, 1H), 1.65(s, 6H), 1.49 (t, J=7.1 Hz, 3H).

Example 148

N-(1-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}cyclobutyl)-2-methylpropane-2-sulfinamide

The title compound was prepared from Intermediate 178 (300 mg, 0.91mmol) and Intermediate 159 (751 mg, 1.09 mmol) in accordance with theMethod described for Example 20 to give, following purification bycolumn chromatography in silica gel (Hexane:EtOAc (from 0 to 100%) thenDCM:MeOH(from 0 to 15%) a yellow solid (600 mg, 98% yield). LC/MS Method3: RT 2.03 minutes, [M+H]⁺=609.

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.32-8.25 (m, 1H), 8.01 (d,J=6.3 Hz, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.76 (t, J=73.6 Hz, 1H), 7.67 (d,J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.53-7.44 (m, 2H), 6.31 (d, J=6.9Hz, 1H), 5.91 (s, 1H), 3.56-3.50 (m, 1H), 2.84 (d, J=13.9 Hz, 1H),2.41-2.45 (m, 2H), 1.75-1.8 (m, 2H), 1.97-2.03 (m, 2H), 1.15 (s, 9H).

Example 149

(7R,14R)-11-[6-(1-aminocyclobutyl)pyridin-3-yl]-1-(difluoromethoxy)-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 148 (600 mg, 0.89 mmol) was dissolved in methanol (4.5 mL) andHCl 4N in dioxane (0.50 mL, 2.0 mmol) was added at room temperature, thereaction was stirred for 5 hours. The solvent was evaporated and thecrude mixture was dissolved in water and DCM. The aqueous layer wasextracted with dichloromethane (x2) and then freeze dried to give thetitle compound as an HCl salt and a white solid (460 mg, 99% yield).LC/MS Method 3: RT 1.65 minutes, [M+H]⁺=505.¹H NMR (300 MHz, DMSO-d⁶) δ8.91 (dd, J=2.4, 0.8 Hz, 1H), 8.89 (bs, 3H, NH₃ ⁺), 8.34-8.15 (m, 2H),7.96-7.76 (m, 3H), 7.73-7.63 (m, 1H), 7.69 (t, J=73.3 Hz, 1H), 7.53-7.49(m, 2H), 6.36 (d, J=7.1 Hz, 1H), 5.34 (d, J=7.1 Hz, 1H), 3.56 (dt,J=14.2, 7.3 Hz, 1H), 2.88 (d, J=13.8 Hz, 1H), 2.63 (q, J=7.3 Hz, 2H),2.35-2.12 (m, 2H), 2.11-1.93 (m, 2H).

Example 150

N-(3-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfinamide

The title compound was prepared from Intermediate 159 (890 mg, 1.65mmol), and Intermediate 179 (500 mg, 1.5 mmol) in accordance with themethod described for Example 20 to give, following purification bycolumn chromatography in silica gel (hexanes: EtOAc from 0 to 100% thenDCM:MeOH from 0 to 15%), a yellow solid (750 mg, 82%). LC/MS Method 3:RT 1.82 minutes, [M+H]⁺=611. ¹H NMR (300 MHz, DMSO-d⁶) δ 8.88 (d, J=2.3Hz, 1H), 8.34-8.22 (m, 1H), 8.08 (dd, J=8.3, 2.4 Hz, 1H), 7.76 (dd,J=5.1, 3.3 Hz, 2H), 7.70-7.63 (m, 1H), 7.67 (t, J=73.3 Hz, 1H), 7.59(dd, J=8.6, 1.7 Hz, 1H), 7.49 (d, J=5.0 Hz, 2H), 6.48 (s, 1H), 6.31 (d,J=7.1 Hz, 1H), 5.24 (d, J=7.1 Hz, 1H), 5.17 (d, J=6.1 Hz, 1H), 5.04-4.75(m, 3H), 3.53 (dt, J=14.3, 7.4 Hz, 1H), 2.83 (d, J=13.8 Hz, 1H), 1.17(d, J=1.2 Hz, 9H).

Example 151

(7R,14R)-11-[6-(3-aminooxetan-3-yl)pyridin-3-yl]-1-(difluoromethoxy)-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Example 150 (249 mg, 0.4077 mmol) was dissolved in methanol (8 mL) andHCl ₄N in dioxane (0.2 mL, 0.8 mmol) was added at 0° C. and the reactionwas kept in the fridge overnight. A saturated aqueous solution of NaHCO₃was added at 0° C. and the reaction mixture was extracted with EtOAc.The combined organic layers were filtered through a phase separator andthe solvent was evaporated to give the title compound (120 mg, 58%) as apale brown solid. LC/MS Method 3: RT 1.49 mins, [M+H]⁺=507. ¹H 1H NMR(300 MHz, DMSO-d6) δ 8.85 (dd, J=2.4, 0.8 Hz, 1H), 8.34-8.21 (m, 1H),8.05 (dd, J=8.3, 2.5 Hz, 1H), 7.80-7.71 (m, 3H), 7.67 (t, J=73.3 Hz,1H), 7.61-7.44 (m, 3H), 6.30 (d, J=7.1 Hz, 1H), 5.24 (d, J=7.0 Hz, 1H),4.93 (d, J=5.6 Hz, 2H), 4.59 (d, J=5.6 Hz, 2H), 3.60-3.44 (m, 1H), 2.83(d, J=13.8 Hz, 1H).

Example 152

N-(3-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfinamide

The title compound was obtained as a by-product of the preparation ofExample 150.

LC/MS: RT 1.75 mins (pH 10), [M+H]⁺=594.

¹H NMR 1H NMR (300 MHz, DMSO-d6) δ 9.14 (d, J=6.9 Hz, 1H), 8.88 (s, 1H),8.22 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.78-7.63 (m, 2H), 7.69 (t, J=73.3Hz, 1H), 7.62-7.40 (m, 2H), 6.47 (s, 1H), 6.37 (d, J=6.9 Hz, 1H), 5.17(d, J=6.3 Hz, 1H), 4.93-4.81 (m, 4H), 3.28 (s, 2H), 3.56 (m, 1H), 2.75(d, J=13.2 Hz, 1H), 1.17 (s, 9H).

Example 153

N-(3-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]-1-oxidopyridin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfonamide

To a solution of Example 152 (18 mg, 0.03 mmol) in dichloromethane (0.3mL), 3-chloroperoxybenzoic acid (5.2 mg, 0.03 mmol) was added and thereaction was stirred overnight. More 3-chloroperoxybenzoic acid (10.4mg, 0.060 mmol) was added and the reaction mixture was stirred for 48hours. The reaction mixture was directly purified by columnchromatography on silica gel (hexanes: EtOAc from 0 to 100% thenDCM:MeOH from 0 to 15% to give the title compound as a white solid (12mg, 63% yield). LC/MS Method 3: RT 1.78 mins, [M+H]⁺=626. ¹H NMR (300MHz, DMSO-d6) δ 9.16 (d, J=6.8 Hz, 1H), 8.57 (s, 1H), 8.27-8.18 (m, 1H),7.89 (d, J=13.7 Hz, 1H), 7.77-7.64 (m, 3H), 7.67 (t, J=73.3 Hz, 1H),7.63-7.46 (m, 2H), 6.36 (d, J=7.0 Hz, 1H), 5.02-4.88 (m, 2H), 4.87 (d,J=7.8 Hz, 3H), 3.56 (m, 1H), 2.77 (s, 1H), 1.14 (s, 9H).

Example 154

(7R,14R)-1-(difluoromethoxy)-11-[4-(2,4-dimethyl-1H-imidazol-5-yl)phenyl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 159 (600 mg, 1.24mmol), and 5-bromo-2-pyrrolidin-2-yl-pyridine (352 mg, 1.55 mmol) inaccordance with the Method described for Example 20 to give, followingpurification by column chromatography in silica gel (Hex: EtOAc from 0to 100% then DCM :MeOH with 2% of NH₃ from 0 to 20%) and subsequent SCFpurification, a white solid (20 mg, 3.2% yield). LC/MS Method 3: RT 1.62minutes, [M+H]⁺=505.¹H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J=2.4 Hz, 1H),8.27 (dd, J=5.9, 3.6 Hz, 1H), 8.01-7.93 (m, 1H), 7.78-7.58 (m, 2H), 7.67(t, J=73.3 Hz, 1H), 7.58-7.44 (m, 4H), 6.29 (d, J=7.2 Hz, 1H), 5.24 (d,J=7.2 Hz, 1H), 4.24 (d, J=7.9 Hz, 1H), 3.52 (dt, J=14.0, 7.3 Hz, 1H),3.11-2.87 (m, 2H), 2.83 (d, J=13.7 Hz, 1H), 2.18 (m, 2H), 1.74 (m, 2H).

Example 155

(7R,14R)-1-(difluoromethoxy)-11-[4-(2,4-dimethyl-1H-imidazol-5-yl)phenyl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 159 (466 mg, 0.9622mmol), and Intermediate 180 (200 mg, 0.789 mmol) in accordance with theMethod described for Example 20. The reaction mixture was filtered andthe solid was washed with dicholoromethane and water to give the titlecompound (110 mg, 27% yield) as a white solid. LC/MS Method 3: RT 1.72mins, [M+H]⁺=529. Free base: ¹H NMR (300 MHz, DMSO-d6) δ 8.32-8.23 (m,1H), 7.75-7.64 (m, 2H), 7.68 (t, J=73.3 Hz, 1H), 7.63 (s, 4H), 7.57-7.46(m, 3H), 6.29 (d, J=7.1 Hz, 1H), 5.23 (d, J=7.1 Hz, 1H), 3.58-3.46 (m,1H), 2.82 (d, J=13.8 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H).

Example 156

(7R,14R)-1-(difluoromethoxy)-11-[4-(2,4-dimethyl-1H-imidazol-5-yl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 171 (114 mg, 0.2196mmol), and Intermediate 180 (50 mg, 0.2 mmol) in accordance with theMethod described for Example 20. The reaction mixture was diluted indicholoromethane:MeOH (10%) and extracted with water. The aqueous layerwas extracted with dichloromethane:MeOH (10%) five times and thecombined organic layer was filtered through a phase separator and thesolvent was evaporated in vacuo. The solid obtained was triturated indichloromethane and water to give the title compound (75 mg, 73% yield)as a yellow solid. HCl in methanol was added and the solid was freezedried to give the HCl salt of the title compound. LC/MS Method 3: RT1.65 mins, [M+H]⁺=512.

¹H NMR (300 MHz, DMSO-d⁶) 1H NMR (300 MHz, DMSO-d6) δ 14.24 (s, 1H),14.13 (s, 1H), 9.15 (d, J=6.8 Hz, 1H), 8.24 (t, J=4.7 Hz, 1H), 7.85-7.64(m, 5H), 7.68 (t, J=73.3 Hz, 1H), 7.62-7.47 (m, 3H), 6.37 (d, J=6.9 Hz,1H), 4.91 (t, J=6.6 Hz, 1H), 3.50-3.45 (m, 1H), 2.78 (m, 1H), 2.61 (s,3H), 2.46 (s, 3H).

Example 157

[(6R,7E,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methano-7λ-4-benzimidazo[2,1-c][1,4]benzothiazepin-7(12H)-ylidene]cyanamide

To a solution of Example 88 (200 mg, 0.55 mmol) and cyanamide (34 mg,0.81 mmol) in acetonitrile (5 mL) at 0° C., was added iodobenzenediacetate (388 mg, 1.21 mmol). The reaction was stirred for 3 hours at0° C. The solvent was evaporated and the crude mixture was purified bycolumn chromatography on silica gel, hexane:EtOAc (0 to 100%) to givethe title compound (145 mg) as a yellow solid. LC/MS Method 3: RT 1.98mins, [M+H]⁺=405. ¹H NMR (300 MHz, DMSO-d⁶) δ 7.75-7.62 (m, 3H), 7.57(t, J=73.1 Hz, 1H), 7.68-7.50 (m, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.27 (dd,J=8.7, 2.1 Hz, 1H), 6.24 (t, J=2.9 Hz, 1H), 5.85 (dd, J=3.2, 2.1 Hz,1H), 3.60 (t, J=3.5 Hz, 2H).

Example 158

N-(2-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)methanesulfonamide

To a solution of Example 62 (350 mg, 0.66 mmol) cooled to 0° C. in DCM(5 mL) was added sequentially, 4-dimethylaminopyridine (0.1 equiv.,0.066 mmol), di-isopropylethylamine (2.2 equiv., 1.45 mmol) followed bydrop wise addition of methane sulphonyl chloride (1.1 equiv., 0.73 mmol)and the mixture allowed to stir at ambient temperature for 2 hours. Thereaction mixture was quenched by addition of water (20 mL), the organicphase separated, dried over sodium sulphate, filtered and the solventsremoved in vacuo. The crude residue was purified by preparative HPLC toafford the title compound as an off white solid (200 mg). ¹H NMR (300MHz, DMSO-d⁶) δ 9.08 (s, 2H), 8.27 (t, J=4.7 Hz, 1H), 8.01-7.72 (m, 2H),7.71-7.59 (m, 1H), 7.57-7.35 (m, 3H), 6.31 (d, J=7.1 Hz, 1H), 5.25 (d,J=7.1 Hz, 1H), 3.53 (dt, J=14.1, 7.3 Hz, 1H), 2.86 (m, 4H), 1.70 (s,6H). LCMS Method 3 RT =1.85 minutes (M+H)⁺572, LCMS Method 4 RT =1.79minutes (M+H)⁺572.

Example 159

N-(2-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)acetamide

The title compound was synthesised from Example 62 (350 mg, 0.66 mmol)and acetyl chloride (1.1 eq, 0.73 mmol) in accordance with the Methoddescribed for Example 158. Purification by preparative HPLC gave an offwhite solid (50 mg). ¹H NMR (300 MHz, DMSO-d⁶) δ 8.99 (s, 2H), 8.39-8.13(m, 2H), 8.01-7.66 (m, 3H), 7.61 (dd, J=8.5, 1.8 Hz, 1H), 7.53-7.41 (m,2H), 6.30 (d, J=7.1 Hz, 1H), 5.25 (d, J=7.1 Hz, 1H), 3.53 (dt, J=14.1,7.3 Hz, 1H), 2.84 (d, J=13.8 Hz, 1H), 1.80 (s, 3H), 1.60 (s, 6H). LCMSMethod 4 RT=1.62 minutes 536 (M+H)⁺. LCMS Method 3 RT=1.68 minutes 536(M+H)⁺

Example 160

(7R,14R)-1-(difluoromethoxy)-11-[4-(pyrrolidin-2-yl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 182 (275 mg, 0.42 mmol) was dissolved in HCl/dioxane (4M)(10 mL) and stirred for 3 hrs at room temperature. After this time thesolution was evaporated in vacuo. The mixture was separated between DCM(20 mL) and aqueous HCl (0.5M) (20 mL) and the DCM layer was discarded.The aqueous layer was then made basic with sodium carbonate solution andthen extracted into DCM (2×50 mL) and the combined organics were dried(phase separator) and evaporated in vacuo. to provide the title compoundas the HCl salt (90 mg, 44%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.13 (d, J=6.8Hz, 1H), 8.23 (dd, J=5.9, 3.6 Hz, 1H), 7.70-7.61 (m, 2H), 7.60-7.37 (m,7H), 6.33 (d, J=7.0 Hz, 1H), 4.87 (t, J=6.7 Hz, 1H), 4.06 (t, J=7.6 Hz,1H), 3.48 (dt, J=13.5, 7.2 Hz, 1H), 3.11-2.82 (m, 1H), 2.73 (d, J=13.4Hz, 1H), 2.14 (dtd, J=12.1, 7.5, 4.8 Hz, 1H), 1.77 (dq, J=13.2, 7.8, 7.4Hz, 1H), 1.60-1.41 (m, 1H), 0.91-0.76 (m, 1H).

LC/MS Method 3: RT 1.76 minutes, m/z 487.2

Example 161

(7R,14R)-1-(difluoromethoxy)-6-trideutero-methyl-11-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 110 (350 mg, 0.89mmol) and [2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]boronic acid (296 mg,1.33 mmol) in accordance with the Method described for Example 20. Theproduct was purified by crystallisation from EtOAc to afford the titlecompound (245 mg, 51%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (s, 2H), 8.26(dd, J=6.2, 3.2 Hz, 1H), 8.14 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.60 (d,J=1.7 Hz, 1H), 7.56-7.41 (m, 3H), 6.28 (d, J=7.1 Hz, 1H), 5.23 (d, J=7.1Hz, 1H), 4.22 (s, 2H), 3.96 (t, J=5.4 Hz, 2H), 3.60-3.42 (m, 2H), 3.30(s, 1H), 2.82 (d, J=13.7 Hz, 1H). LC/MS Method 3: RT 1.50 minutes, m/z535.2

Example 162

(7R,14R)-1-(difluoromethoxy)-6-methyl-11-[2-(5-oxo-1,4-diazepan-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 110 (350 mg, 0.89mmol) and [2-(5-oxo-1,4-diazepan-1-yl)pyrimidin-5-yl]boronic acid (315mg, 1.33 mmol) in accordance with the Method described for Example 20.Purification by flash chromatography on silica gel (0 to 10% gradient ofMeOH in DCM) and then crystallisation from EtOAc afforded the titlecompound (245 mg, 51%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (s, 2H), 8.27(dd, J=5.9, 3.5 Hz, 1H), 7.76-7.65 (m, 2H), 7.60 (d, J=1.7 Hz, 1H),7.56-7.40 (m, 3H), 6.27 (d, J=7.1 Hz, 1H), 5.22 (d, J=7.1 Hz, 1H), 3.97(q, J=4.3, 3.8 Hz, 4H), 3.50 (dt, J=14.1, 7.2 Hz, 1H), 3.24 (d, J=6.9Hz, 2H), 2.82 (d, J=13.8 Hz, 1H), 2.54 (s, 2H). LC/MS Method 3: RT 1.63minutes, m/z 549.2

Example 163

(7R,14R)-11-[4-(2-aminopropan-2-yl)phenyl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 182(a) (0.10 g, 0.13 mmol) (75% pure) was dissolved in HCldioxane (4M, 10 mL) and stirred for 18 hrs at r.t. and before beingevaporated in vacuo. The mixture was separated between DCM (20 mL) andsodium carbonate (20 mL) and the organic layer was then dried (phaseseparator) and evaporated in vacuo. Purification by flash chromatographyon silica gel (0 to 10% gradient of MeOH in DCM) and freeze drying fromHCl (0.5M) to obtain the HCl salt of the title compound as a whitepowder. (36 mg, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.13 (d, J=6.8 Hz,1H), 8.23 (dd, J=6.0, 3.5 Hz, 1H), 7.72-7.54 (m, 5H), 7.59-7.32 (m,7H),6.34 (d, J=7.1 Hz, 1H), 4.87 (t, J=6.7 Hz, 1H), 3.60-3.43 (m, 1H), 2.73(d, J=13.2 Hz, 1H), 1.44 (s, 6H), 1.24 (s, 1H). LC/MS Method 3: RT 1.80minutes, m/z 475.2

Example 164

(7R,14R)-1-(difluoromethoxy)-11-[2-(3-hydroxy-3-methylazetidin-1-yl)-4-methylpyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound can be prepared from Intermediate 171 (0.35 g, 0.93mmol, leg) and1-(5-bromo-4-methyl-pyrimidin-2-yl)-3-methyl-azetidin-3-ol (leq) inaccordance with the Method described for Example 137. The product waspurified by column chromatography on silica gel (EtOAc in DCM (0 to 100%gradient) and then MeOH in EtOAc (0 to15% gradient)) to afford the freebase of the title compound as a brown solid. The solid could be furtherpurified by dissolving into aqueous 0.5M HCl (20 mL) and then washingthe aqueous solution with DCM (2×25 mL). Sodium carbonate solution wasthen added until precipitation was observed and the mixture extractedinto DCM (3×50 mL). The organics were dried (phase separator) andevaporated in vacuo before being again dissolved into aqueous 0.5M HCland freeze dried to afford the HCl salt of the title compound (215 mg,42%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (d, J=6.9 Hz, 1H), 8.23 (dd,J=5.8, 3.6 Hz, 1H), 8.15 (s, 1H), 7.71-7.45 (m, 4H), 7.41-7.27 (m, 1H),7.17 (dd, J=8.4, 1.7 Hz, 1H), 6.31 (d, J=7.1 Hz, 1H), 4.90 (t, J=6.7 Hz,1H), 3.93 (d, J=1.9 Hz, 4H), 3.60-3.32 (m, 1H), 2.74 (d, J=13.3 Hz, 1H),2.26 (s, 3H), 1.45 (s, 3H).

LC/MS Method 3: RT 1.58 minutes, m/z 519.2.

Example 165

(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-trideutero-methyl-11-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 187 (120 mg, 0.18 mmol) was suspended in 2-propanol (20 mL)and treated with hydrochloric acid (5 ml, 20 mmol, 4M in 1,4-dioxane)and stirred for 3 hours at ambient temperature. The solvent was removedin vacuo and the residual solid used without further purification.

The residue was suspended in acetonitrile (10 ml), cooled to 0° C. and4-methylmorpholine (0.1 mL, 0.9 mmol) added followed by COMU (87 mg,0.197 mmol) and the mixture allowed to stir and reach ambienttemperature. After 1 hour the mixture was diluted with water (25 mL) andextracted into EtOAc (3×20 mL). Combined organics were washed with water(20 mL) and dried (Na₂SO₄), filtered and concentrated in vacuo to give acrude beige solid. Purification by column chromatography eluting with 0to 100% DCM/EtOAc and then a gradient of DCM/MeOH 1 to 10% before freezedrying afforded the title compound as a white solid (46 mg, 47%). ¹H NMR(300 MHz, DMSO-d₆) δ 8.56 (t, J=1.7 Hz, 2H), 8.27 (dd, J=7.0, 2.5 Hz,1H), 8.15 (s, 1H), 7.66-7.56 (m, 2H), 7.56-7.35 (m, 3H), 6.27 (d, J=7.0Hz, 1H), 5.24 (d, J=7.1 Hz, 1H), 4.23 (s, 2H), 3.96 (t, J=5.4 Hz, 2H),3.50 (d, J=7.2 Hz, 1H), 3.31 (s, 2H), 2.82 (d, J=13.8 Hz, 1H). LC/MSMethod 3: RT 1.52 minutes, m/z 553.2

General Method A: Suzuki Coupling between Intermediate 171 and ArylBromides

To a degassed suspension of Intermediate 171 (0.08 mmo1), Pd2dba3(5%mol), tricyclohexylphosphonium tetrafluoroborate (12%mol) andK₃PO₄(2.5eq) in 1,4-dioxane/water (2m1/0.1 mL)was added the appropriatearyl bromide (1.5eq). The resultant mixture was stirred in an Anton Paarmicrowave at 110° C. for 2 hours and then concentrated in vacuo. Theresidue was dissolved into EtOAc, washed with water, concentrated invacuo and subsequently purified by preparative HPLC in basic mode toafford the title compounds described in Table 1.

TABLE 1 EXAMPLES 166 to 173 LCMS Method 4 Example Structure IUPAC_NAMEMass RT (mins) 166

(7R,14R)-1-(difluoromethoxy)-11-[2-(1-oxidothiomorpholin-4-yl)pyrimidin- 5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 537.1 3.6 167

(7R,14R)-11-[2-(4,4-difluoro-1- hydroxycyclohexyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one 554.1 4.67 168

(7R,14R)-1-(difluoromethoxy)-11-[2- (3-hydroxy-1,1-dioxidotetrahydrothiophen-3- yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 554.1 3.66 169

(3R)-3-{5-[(7R,14R)-1- (difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin- 2-yl}-3-hydroxytetrahydrothiophenium-1-olate 538.1 3.35 170

(3S)-3-{5-[(7R,14R)-1- (difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin- 2-yl}-3-hydroxytetrahydrothiophenium-1-olate 538.1 3.33 171

(7R,14R)-1-(difluoromethoxy)-11-[2- (3-hydroxyoxetan-3-yl)pyrimidin-5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one 492.1 3.58 172

(7R,14R)-1-(difluoromethoxy)-11-{1-[1-(methylsulfonyl)azetidin-3-yl]-1H- pyrazol-4-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 541.1 3.8 173

(7R,14R)-1-(difluoromethoxy)-11-(2- hydroxypyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 436.1 3.06

General Method B: Suzuki Coupling between Example 11 and Aryl BoronicAcids

To a degassed suspension of Example 11 (0 .1 mmol), Pd₂dba₃ (5%mol),tricyclohexylphosphonium tetrafluoroborate (12%mol) and K₃PO₄(2.5eq) in1,4-dioxane/water (2ml/0.1 mL)was added the appropriate aryl boronicacid or pinacalato ester (1.5eq). The resultant mixture was stirred inan Anton Paar microwave at 110° C. for 2 hours and then concentrated invacuo. The residue was dissolved into EtOAc, washed with water,concentrated in vacuo and subsequently purified by preparative HPLC inbasic mode to afford the title compounds described in Table 2.

TABLE 2 EXAMPLES 174 to 185 LCMS Method 4 Example Structure IUPAC_NAMEMass RT (mins) 174

(7R,14R)-1-(difluoromethoxy)-11-[2- (1,4-dihydroxy-4-methylcyclohexyl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one548.2 3.88 175

2-{5-[(7R,14R)-1-(difluoromethoxy)-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-2-methylpropanenitrile 487.2 4.49 176

1-{5-[(7R,14R)-1-(difluoromethoxy)-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-3-methylazetidine-3-carbonitrile 514.2 4.18 177

(7R,14R)-1-(difluoromethoxy)-11-{2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyrimidin-5-yl}-6,7-dihydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one 517.1 3.94 178

(7R,14R)-1-(difluoromethoxy)-11-[2- (thiomorpholin-4-yl)pyrimidin-5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one 521.1 4.86 179

(7R,14R)-1-(difluoromethoxy)-11-{2- [3-(2-hydroxypropan-2-yl)azetidin-1-yl]pyrimidin-5-yl}-6,7-dihydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one 533.2 3.86 180

(7R,14R)-11-[2-(3,3-difluoroazetidin-1-yl)pyrimidin-5-yl]-1-(difluoromethoxy)- 6,7-dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 511.1 4.47 181

(7R,14R)-1-(difluoromethoxy)-11-[2- (3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one 531.2 4.39 182

(7R,14R)-1-(difluoromethoxy)-11-[2- (7-oxo-3,6-diazabicyclo[3.2.2]non-3-yl)pyrimidin-5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one 558.2 3.73 183

(7R,14R)-1-(difluoromethoxy)-11-[2- (1,1-dioxidothiomorpholin-4-yl)pyrimidin-5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one 553.1 4.02 184

(7R,14R)-1-(difluoromethoxy)-11-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)- 6,7-dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 449.1 3.48 185

(7R,14R)-1-(difluoromethoxy)-11-[2-(tetrahydro-2H-pyran-4-yl)pyrimidin-5- yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 504.1 4.05

Example 186

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-10-fluoro-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 191 (420 mg, 0.70 mmol) was dissolved in HCl (4M in1,4-dioxane) 10 mL and stirred for 3 hours at room temperature. After 3hours the solution was concentrated in vacuo.

The mixture was separated between DCM and aqueous HCl (0.5M) and the DCMlayer was discarded. The aqueous layer was then made basic with sodiumcarbonate solution and then extracted with DCM (3×50 mL) and thecombined organics were dried (MgSO₄), filtered and evaporated in vacuo.The product was purified by column chromatography on silica eluting with0 to 15% MeOH in DCM to afford an off-white solid. The compound wasfreeze dried with an equivalent of hydrochloric acid to afford the titlecompound as an HCl salt (275 mg, 72%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (d, J=1.6 Hz, 2H), 8.61 (bs, 3H, NH3⁺),8.29 (dd, J=7.5, 1.9 Hz, 1H), 7.82-7.70 (m, 1H), 7.60 (d, J=6.7 Hz, 2H),7.57-7.45 (m, 2H), 6.29 (d, J=7.1 Hz, 1H), 5.29 (d, J=7.2 Hz, 1H), 3.54(dt, J=14.0, 7.5 Hz, 1H), 2.86 (d, J=13.8 Hz, 1H), 1.70 (s, 6H). LC/MSMethod 3: RT 1.67 minutes, m/z 512.2

Example 187

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ylphosphate, disodium salt

To a solution of Intermediate 192 (31.0 g, 41.0 mmol) in a mixture ofethanol (450 mL) and sodium hydroxide (410 mL, 82.0 mmol, 0.200 mol/L)was added 10% Pd/C (3.10 μ). The reaction mixture was degassed undervacuum and placed under a hydrogen atmosphere using a balloon. Thereaction mixture was stirred vigorously until LCMS analysis showed thereaction was complete. It was necessary to add a further portion of Pd/Ccatalyst (775 mg, 2.5%w/w) after 1 hour and the mixture stirred underhydrogen for a further 30 minutes. The reaction mixture was degassedwith nitrogen, filtered through a pad of celite which was washed withEtOH/H₂O (1/1, 1000 mL), collecting the colourless eluent. The ethanolwas removed in vacuo and the aqueous reduced to ˜400 mL volume in vacuo.The aqueous was washed with dichloromethane (3×250 mL) which wasdiscarded, before further concentrating the aqueous solution in vacuo toa 200 mL volume. The aqueous layer was stirred with phosphonics MTUresin (15μ) for 2.5 hours to remove palladium residues. After filtrationto remove the resin, the aqueous was concentrated down to ˜100 mL invacuo and then freeze dried to give the title compound as a white solid(23.15 g, 91%). ¹H NMR: (D₂O, 300 MHz) 1.76 (s, 6H), 2.61 (d, 1H, J=13.6Hz), 3.16 (m, 1H), 4.83 (d, 1H, J=6.5 Hz), 6.19 (d, 1H, J=7.0 Hz), 6.84(m, 1H), 7.05 (t, 1H, J=73.3 Hz) 7.12 (m, 1H), 7.30 (m, 2H), 7.93 (dd,1H, J=8.2, 0.9 Hz), 8.56 (d, 2H, J=1.2 Hz). LC/MS Method 3: RT 1.00minutes, m/z 576.

Example 188

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ylphosphate, disodium salt

To a solution of Intermediate 193 (3.2 g, 4.2 mmol) in a mixture ofethanol (60 mL) and sodium hydroxide solution (330 mg in 42 mL of water)was added 10% Pd/C (480 mg).

The reaction was degassed and placed under a hydrogen atmosphere, andstirred vigorously for 40 minutes before the reaction completed. Thereaction mixture was filtered through a pad of celite, washed withEtOH/H₂O (1:1, 200 mL), and most of the EtOH was removed in vacuo. Theaqueous was washed with DCM (5×50 mL) before being further concentratedin vacuo, and treated with MTU resin (1.5 g) to remove palladiumimpurities and stirred for 1.5 hours before filtration through a pad ofcelite. The water was removed in vacuo and further dried onfreezer-drier to give the desired product as the disodium salt (2.43 g,92%). ¹H NMR (D₂O, 400 MHz) δ 8.65 (s, 2H), 8.01 (d, J=8.1 Hz, 1H), 7.43(d, J=6.7 Hz, 1H), 7.3-6.9 (m, 4H), 6.16 (d, J=7.1 Hz, 1H), 5.04 (d,J=7.2 Hz, 1H), 3.34 (s, 3H), 3.27 (m, 1H), 2.67 (d, J=14.0 Hz, 1H), 1.76(s, 6H). LC/MS Method 3: ES⁺(M+H)⁺590, retention time 0.91 minutes.

Example 189

(7R,14R)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-1-(trifluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

A 0.6M solution of phenol in anhydrous DMSO (1.15 ml, 0.69 mmol) wasadded to a solution of Intermediate 206 (0.300 g, 0.57 mmol) inanhydrous DMSO (5 ml). Potassium carbonate (0.120 g, 0.86 mmol), dried4A molecular sieves (0.360 μ),dichloro-[bis(dicyclohexylphosphino)propane]palladium(II) (0.035 g,0.057 mmo1) were added and the reaction mixture was heated to 100° C.under 3 bars of carbon monoxide for 48 hours.

Water (50 ml) was added and the resulting mixture was extracted withEtOAc (1×150 ml). The organic phase was then washed with brine (2×300ml), dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting crude residue was purified by SiO₂ flashchromatography with DCM/MeOH (100/0 to 95/5) as eluent to give a brownsolid. The solid was treated with iPr₂O (10 ml), filtered, and driedunder reduced pressure at 45° C. to give the title compound (0.110 g,37% yield).

LCMS (Method 20, ES+) RT 1.02 min., 514 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6) 1.55 (s, 6H), 2.82 (d, J=13.5 Hz, 1H), 3.51 (m, 1H), 4.95 (t,J=6.9 Hz, 1H), 5.15 (s, 1H), 6.32 (d, J=7.2 Hz, 1H), 7.42 (d, J=6.8 Hz,1H), 7.58 (t, J=8.3 Hz, 1H), 7.69 (d, J=11.5 Hz, 1H), 7.72 (m, 1H), 8.38(dd, J=1.3 and 8.3 Hz, 1H), 8.92 (d, J=1.8 Hz, 2H), 9.21 (d, J=6.9 Hz,1H).

Example 190

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 208 (0.265 g, 0.55mmol) in accordance with the synthetic procedure described forExample191. Purification by SiO₂ flash chromatography with DCM/MeOH(100/0 to 95/5) as eluent to give a pink solid.

This solid was treated with iPr₂O (10 ml) and the resulting suspensionwas filtered, and before being dried under reduced pressure at 45° C.,the isolated solid was washed with iPr₂O (2×10 ml) and with pentane(3×10 ml) to give the title compound (0.082 g, 36% yield).

LCMS (Method 20, ES+) RT 0.88 min., 473 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6) 1.05 (s, 6H), 2.66 (d, J=13.5 Hz, 1H), 2.69 (m, 1H), 3.40 (m,1H), 3.71-3.85 (m, 4H), 4.38 (s, 1H), 4.77 (t, J=6.9 Hz, 1H), 6.18 (d,J=7.2 Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 7.27 (d, J=13.2 Hz, 1H), 7.49 (m,2H), 7.63 (t, J=74.3 Hz, 1H), 8.21 (m, 1H), 9.05 (d, J=6.9 Hz, 1H).

Example 191

(7R,14R)-11-((2-aminopropan-2-yl)phenyl)-10-fluoro-1-(trifluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 210 (0.195 g, 0.38mmol) in accordance with the synthetic procedure described for Example189 to give after purification by SiO₂ flash chromatography withDCM/MeOH/NH₄OH (100/0/0 to 94.5/5/0.5) as eluent followed flashchromatography on amino modified silica eluting with DCM/MeOH (100/0 to98/8) as eluent and subsequent trituration with iPr₂O to give (0.055 g,26% yield).

LCMS (Method 20, ES+) RT 0.65 min., 511 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6) 1.42 (s, 6H), 2.25 (broad m, 2H), 2.81 (d, J=13.5 Hz, 1H), 3.50(m, 1H), 4.91 (t, J=6.9 Hz, 1H), 6.30 (d, J=7.2 Hz, 1H), 7.32 (d, J=7.0Hz, 1H), 7.40 (broad d, J=8.5 Hz, 2H), 7.54 (d, J=12.0 Hz, 1H), 7.57 (t,J=8.3 Hz, 1H), 7.63 (d, J=8.5 Hz, 2H), 7.70 (broad d, J=8.3 Hz, 1H),8.49 (dd, J=1.2 and 8.3 Hz, 1H), 9.20 (d, J=6.9 Hz, 1H).

Example 192

(7R,14R)-11-((2-aminopropan-2-yl)phenyl)-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 212 (0.240 g, 0.48mmol) in accordance with the synthetic procedure described forExample191. Purification by SiO₂ flash chromatography withDCM/MeOH/NH₄OH (100/0/0 to 94.5/5/0.5) as eluent gave a pink solid. Thissolid was purified with preparative HPLC using C18 Nucleodur gravity250×4.6 mm Macherey-Nagel column and a gradient of acetonitrile (B) inwater (A) containing 0.1% TFA (B/A 5/95 to 1/1 in 23min, 1 ml/min) toafford the title compound (0.041 g, 17% yield).

LCMS (Method 20, ES+) RT 0.60 min., 493 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6) 1.68 (s, 6H), 2,74 (d, J=13.5 Hz, 1H), 3,48 (m, 1H), 4,90 (t,J=6.9 Hz, 1H), 6,31 (d, J=7.2 Hz, 1H), 7.47-7.54 (m, 3H), 7.58 (t,J=73.4 Hz, 1H), 7.59 (m, 3H), 7,65 (d, J=8.5 Hz, 2H), 8,24 (m, 1H), 9.15(d, J=6.9 Hz, 1H).

Example 193

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4-(tetrahydrofuran-3-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Example 1 (100 mg, 0,202 mmol),tetrahydrofuran-3-sulfonyl chloride (106 mg, 0,6026 mmol) and[Ir[DF(CF₃)PPY]₂(DTBPY)]PF₆ (4,5 mg, 0,0040 mmol) in acetonitrile/TFA(1/1) (2 mL), following the General procedure for the late stagetrifluoromethylation described for Example 107. The crude reaction waspurified by LC-2D MS chromatography in acidic mode (formic acid) Method14 yielding to 6,6 mg (6%) of the title compound as a white solid. LCMSMethod/5 (ES+) RT 5.23 min., 566 (M+H)+.¹H NMR (400 MHz, DMSO-d6) δ 9.05(d, J=6.8 Hz, 1H), 8.62 (s, 1H), 8.26 (dd, J=6.3, 3.1 Hz, 1H), 7.62 (d,J=10.6 Hz, 1H), 7.53-7.47 (m, 2H), 7.46 (t, J=73.6 Hz, 1H), 7.36 (t,J=5.9 Hz, 1H), 6.34 (d, J=7.1 Hz, 1H), 5.04-4.77 (m, 2H), 4.02-3.80 (m,2H), 3.80-3.60 (m, 2H), 3.52 (dd, J=13.8, 6.9 Hz, 1H), 3.42-3.27 (m,1H), 2.75 (d, J=13.5 Hz, 1H), 2.28-2.08 (m, 1H), 2.07-1.90 (m, 1H), 1.57(s, 6H).

Example 194

(7R,14R)-1-(difluoromethoxy)-11-[4-(difluoromethyl)-2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Example 1 (100 mg, 0,202 mmol),difluoromethanesulfonyl chloride (54 μL, 0,61 mmol) and[IR[DF(CF₃)PPY]₂(DTBPY)]PF₆ (4,5 mg, 0,0040 mmol) in acetonitrile/TFA(1/1) (2 mL), following the General procedure for the late stagetrifluoromethylation described for Example 107. The crude reaction wastaken up in methanol (4 mL) before addition of potassium carbonate (170mg, 1,218 mmol) and stirred at room temperature for 1 hour.

The reaction mixture was filtered and concentrated under vacuum. Theresidue was purified by LC-2D MS chromatography Method 14 yielding to13.7 mg (13%) of the title compound as a white solid. LCMS Method/5(ES+) RT 5.40 min., 546 (M+H)⁺.¹H NMR (400 MHz, DMSO-d6) δ 9.17 (d,J=6.8 Hz, 1H), 8.98 (s, 1H), 8.25 (dd, J=6.6, 2.1 Hz, 1H), 7.67 (d,J=10.3 Hz, 1H), 7.55-7.49 (m, 2H), 7.48 (t, J=73.1 Hz, 1H), 7.44 (d,J=6.5 Hz, 1H), 6.83 (t, J=53.0 Hz, 1H), 6.33 (d, J=7.0 Hz, 1H), 5.28 (s,1H), 4.93 (t, J=6.6 Hz, 1H), 3.51 (dd, J=13.6, 7.0 Hz, 1H), 2.76 (d,J=13.4 Hz, 1H), 1.60 (s, 6H).

Example 195

(7R,14R)-1-(difluoromethoxy)-6-ethyl-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 194 (5 mg, 0,012 mmol)and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester(6.58 mg, 0,024 mmol), following the synthetic protocol described forExample 101. TPutification over silica gel (heptane/ethyl acetate 25/75to 0/100) to afforded 3 mg (48%) of the title compound as an off-whitesolid. LCMS Method 3 (ES+): RT 2.32 min, [M+H]⁺=520.2.

Example 196

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 150 (7 mg, 0.012 mmol) was added to a solution ofDCM/trifluoroacetic acid (1:1, 0.17 mL). The reaction mixture wasstirred at ambient temperature for 1 hour before addition of a saturatedaqueous solution of NaHCO₃ (1 mL). The aqueous layer was extracted withDCM (2×2 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo, yielding 6 mg (100%) of the titlecompound as a white solid. LCMS Method 3 (ES+): RT 3.04 minutes,[M+H]+=491.

Example 197

(7R,14R)-1-(difluoromethoxy)-11-(2-{2-[di(prop-2-en-1-yl)amino]propan-2-yl}pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]boronic acid pinacol ester, andExample 23 in accordance with General Method B to give, followingpurification by preparative HPLC, a white solid (30 mg, 15% yield).LC/MS Method 3: RT 1.84 mins (pH 10), [M+H]+=568. ¹H NMR (300 MHz,DMSO-d6) δ 8.71 (s, 2H), 8.12 (s, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.65-7.25(m, 4H), 7.33 (t, J=8.5 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.10 (d, J=4.3Hz, 1H), 5.93 (d, J=3.9 Hz, 1H), 4.23 (s, 2H), 3.96 (t, J=5.4 Hz, 2H),3.35-3.28 (m, 2H), 3.32-3.15 (m, 1H), 3.06 (s, 3H), 2.66 (d, J=12.2 Hz,1H).

Example 198

(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-11-[6-(S-methylsulfonimidoyl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 159 (0.5 g, 1.03 mmol)in 1,4-dioxane (10 mL, 116 mmol) andN-[(5-bromopyridin-2-yl)(methyl)oxido-k6-sulfanylidene]-2,2,2-trifluoroacetamide(0.42 g, 1.29 mmol) in accordance with General Method A. Purification byflash chromatography on silica in ethyl acetate/DCM (gradient from 0 to100%) and then methanol in ethyl acetate (0 to 15%) gave the titlecompound as a white solid (50 mg, 9%). ¹H NMR (400 MHz, DMSO-d6) δ 8.96(d, J=2.2 Hz, 1H), 8.30 (m, 2H), 8.15 (d, J=8.2 Hz, 1H), 7.79 (m, 2H),7.71-7.59 (m, 2H), 7.59-7.46 (m, 2H), 6.32 (d, J=7.1 Hz, 1H), 5.26 (d,J=7.2 Hz, 1H), 4.47 (s, 1H), 3.54 (dt, J=14.1, 7.2 Hz, 1H), 3.22 (d,J=1.1 Hz, 3H), 2.85 (d, J=13.8 Hz, 1H). LC/MS Method 3: RT 1.45 mins (pH10), [M+H]+=513.2

Example 199

(7R,14R)-1-(difluoromethoxy)-11-[6-(S-methylsulfonimidoyl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

The title compound was prepared from Intermediate 171 (250 mg, 0.43mmol) and ,N-[(5-bromopyridin-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(216 mg, 0.652 mmol), in accordance with General Method A. Purificationby preparative HPLC gave the title compound (66 mg, 31%) as a whitesolid. LC/MS Method 3: ESI MH+496, retention time 0.76 minutes (pH 10).¹H NMR (300 MHz, DMSO-d⁶) δ 9.15 (d, J=6.8 Hz, 1H), 8.96 (dd, J=2.3, 0.8Hz, 1H), 8.31 (dd, J=8.3, 2.3 Hz, 1H), 8.23 (dd, J=5.8, 3.6 Hz, 1H),8.14 (dd, J=8.3, 0.8 Hz, 1H), 7.95-7.66 (m, 3H), 7.61 (dd, J=8.6, 1.7Hz, 1H), 7.55-7.47 (m, 2H), 6.38 (d, J=7.0 Hz, 1H), 4.91 (t, J=6.8 Hz,1H), 4.47 (s, 1H), 3.50 (dt, J=13.6, 7.0 Hz, 1H), 3.21 (d, J=1.1 Hz,3H), 2.76 (d, J=13.4 Hz, 1H).

Example 200

(7R,14R)-1-(difluoromethoxy)-11-(2-{2-[di(prop-2-en-1-yl)amino]propan-2-yl}pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 171 (400 mg, 0.86 mmol), Intermediate 213 (254 mg, 0.86mmol), tris(dibenzylideneacetone)-dipalladium(0) (39.2 mg,0.043 mmol)and tricyclohexylphosphonium tetrafluoroborate (32.5 mg, 0.086 mmol)were added to a microwave tube and dioxane (2.5 ml) was added, followedby potassium phosphate tribasic (562 mg, 2.57 mmol) dissolved in water(0.5 ml). The mixture was degassed and refilled with nitrogen thenheated to 105° C. for 2 hours. The mixture was partitioned between ethylacetate and water (50 ml) each. The organic layer was dried (sodiumsulfate), filtered and concentrated in vacuo. Purification by flashchromatography (silica, 0 to 10% methanol in dichloromethane) affordedthe title compound as an off-white solid (200 mg, 42% yield). LCMSMethod 3 (ES+) RT 2.62 minutes, 557.2 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d⁶)δ 9.14 (d, J=6.8 Hz, 1H), 9.03 (s, 2H), 8.23 (dd, J=6.4, 3.1 Hz, 1H),7.83-7.70 (m, 2H), 7.68 (t, JH-F =73.4 Hz, 1H), 7.60 (dd, J=8.5, 1.8 Hz,1H), 7.55-7.45 (m, 2H), 6.37 (d, J=7.1 Hz, 1H), 5.87-5.60 (m, 2H), 5.05(dt, J=17.1, 1.8 Hz, 2H), 4.95-4.82 (m, 3H), 3.61-3.41 (m, 1H), 3.22(dt, J=6.0, 1.6 Hz, 4H), 2.75 (d, J=13.4 Hz, 1H), 1.57 (s, 6H).

Example 201

Ammonium2-(5-((7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)propan-2-ylsulfate.

A 4 mL reaction vial was charged with Example 1 (100 mg, 0.202 mmol),sulfur trioxide trimethylamine complex (56.2 mg, 0.404 mmol) andpyridine (1 mL). The vial was closed and heated at 130° C. for 20 hours.After cooling to room temperature, the mixture was concentrated underreduced pressure and the residue was purified by reverse phase HPLC(Reveleris Prep; Detection: UV (220 nm), Column: XSelect™ CSH C18,145×25 mm, Flow: 40 mL/min, Gradient: t₀=5% B, t_(1min)=5% B,t_(2min)=20% B, t_(17min)=60% B, t_(18min)=100% B, Post time: 5 min 100%B, Eluent A: 10mM ammoniumbicarbonate in water (pH=9.0), Eluent B: 99%acetonitrile +1% 10mM ammoniumbicarbonate in water in acetonitrile) toafford the title compound (71 mg, 61%) as a white solid afterlyophilisation of the product fractions.

LCMS (Method 9): RT=1.69 minutes; [M−NH₄ ⁺]⁻=574.

¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (d, J=6.9 Hz, 1H), 8.88 (d, J=1.5 Hz,2H), 8.23 (dd, J=7.7, 1.5 Hz, 1H), 7.66 (d, J=11.5 Hz, 1H), 7.63 (dd,J=72.2, J=1.6 Hz, 1H), 7.57-7.46 (m, 3H), 7.07 (bs, 4H), 6.36 (d, J=7.1Hz, 1H), 4.91 (t, J=6.8 Hz, 1H), 3.54-3.44 (m, 1H), 2.75 (d, J=13.4 Hz,1H), 1.75 (s, 6H).

Example 202

4-((2-(5-((7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)propan-2-yl)oxy)-4-oxobutanoicacid.

A mixture of Example 1(1.5 g, 3.03 mmol), succinic anhydride (1.82 g,18.2 mmol) and 4-dimethylaminopyridine (555 mg, 4.54 mmol) inacetonitrile (20 mL) was heated to reflux temperature for 6 days. Aftercooling to room temperature, the mixture was concentrated under reducedpressure. The residue was partitioned between aqueous HCl solution (1M)and EtOAc and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with aqueous HCl solution (1M) and brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure toafford a brown residue. The material was purified by flash columnchromatography (silica (80 μ); 5-10% MeOH in DCM) to afford the titlecompound (515 mg, 28%) as a white solid after trituration with Et₂O.

LCMS (Method 10): RT=3.09 minutes; [M+H]⁺=596.

¹H NMR (400 MHz, DMSO-d6) δ 12.20 (bs, 1H), 9.16 (d, J=6.8 Hz, 1H), 8.92(d, J=1.6 Hz, 2H), 8.23 (dd, J=6.8, 2.6 Hz, 1H), 7.67 (d, J=11.5 Hz,1H), 7.62 (t, J=72.5 Hz, 1H), 7.57-7.47 (m, 3H), 6.35 (d, J=7.1 Hz, 1H),4.91 (t, J=6.8 Hz, 1H), 3.54-3.44 (m, 1H), 2.75 (d, J=13.4 Hz, 1H),2.58-2.47 (m, 2H, coincides with DMSO), 2.42 (t, J=6.7 Hz, 2H), 1.74 (s,6H).

Example 203 and Example 204

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-(2-((2R*)-hydroxybutan-2-yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-(2-((2S*)-hydroxybutan-2-yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

1M Tetrabutylammonium fluoride (8.46 ml, 8.46 mmol) was added to asolution of Intermediate 216 (0.176 g, 0.28 mmol). The reaction mixturewas stirred at room temperature over 15 days.

Water (50 ml) was added and the resulting mixture was extracted withEtOAc (3×50 ml). The organic phase was washed with brine (50 ml), driedover magnesium sulfate, filtered and concentrated under reducedpressure. The resulting crude residue was purified by SiO₂ flashchromatography with DCM/MeOH (98/2) as eluent to afford the expectedproduct as a mixture of diastereoisomers.

The mixture was purified by preparative chiral HPLC using Chiralcel OD10 μm 250×30 mm with EtOH/MeOH/Triethylamine (50/50/0.1) as eluent andwith 45 ml/min flow in 18 min to afford each pure diastereoisomer.

Diastereomer A Example 203

12.8 mg: Analytical Chrial HPLC Chiralcel OD 10 μm 250×4.6 mm withEtOH/MeOH/Triethylamine (50/50/0.1) as eluant and with 1 ml/min flowover 15 minutes with RT=7.7 min.

LCMS (Method 20, ES+) RT 1.04 min., 510 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) 0.75 (t, J=7 Hz, 3H),1.50 (s, 3H),1.80-2.00(m, 2H),2.75 (d, J=13 Hz, 1H),3.49 (m, 1H),4.90 (t, J=7 Hz, 1H),5.00 (s,1H),6.35 (d, J=7 Hz, 1H),7.50 (m, 2H),7.56 (d, J=6 Hz, 1H),7.62 (t, J=73Hz, 1H),7.68 (d, J=9 Hz, 1 H),8.23 (m, 1H),8.97 (d, J=2 Hz, 1H),9.15 (d,J=6 Hz, 1H).

Diastereomer B Example 204

10.7 mg: Analytical Chiral HPLC Chiralcel OD 10um 250×4.6 mm withEtOH/MeOH/Triethylamine (50/50/0.1) as eluent and with a 1 ml/min flowrate over 15 minutes with RT =12.9 minutes.

LCMS (Method 20, ES+) RT 1.04 min., 510 [M+H]¹.

¹H NMR (400 MHz, DMSO-d₆) 0.75 (t, J=7 Hz, 3H); 1.50 (s, 3H); 1.80 a2.00 (m, 2 H); 2.75 (d, J=13 Hz, 1H); 3.49 (m, 1H); 4.90 (t, J=7 Hz,1H); 5.00 (s, 1H); 6.35 (d, J=7 Hz, 1H); 7.50 (m, 2H); 7.56 (d, J=6 Hz,1H); 7.62 (t, J=73 Hz, 1H); 7.68 (d, J=9 Hz, 1H); 8.23 (m, 1H); 8.97 (d,J=2 Hz, 1H); 9.15 (d, J=6 Hz, 1H).

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. A compound represented byformula (IB), or an N-oxide thereof, or a pharmaceutically acceptablesalt thereof,

wherein —X-Q- represents —O—, —O—C(O)—, —O—C(CH—CN)—, —S—, —SO—, —SO₂—;or —N(R^(g))—, —N(R^(f))—CO—, —N(R^(f))—SO₂—, —O—CH₂—, —CH₂—S—,—CH₂—SO-, —CH₂—SO₂—, —N(R^(g))—CH₂—, —N(R^(f))—C(S)—, —N═S(O)(CH₃)—,—O—C(═CH₂)— or —S(═N—CN)—, any of which groups may be optionallysubstituted by one or more substituents selected from fluoro, methyl,carboxy, trifluoromethyl, methylcarbonyl, deuterated methyl,ethoxycarbonyl, hydroxyisopropyl, and hydroxymethyl; Z representsmethylene; R¹ represents halogen or cyano; or aryl, heteroaryl,(C₃₋₇)cycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl-heteroaryl,(C₄₋₉)heterobicycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl,(C₃₋₇)heterocycloalkenyl, or (C₃₋₇)heterocycloalkenyl-aryl, any of whichgroups may be optionally substituted by one or more substituentsselected from halogen, cyano, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl,difluoromethyl, trifluoromethyl, hydroxy, (hydroxy)(C₁₋₆)alkyl, amino,(amino)(C₁₋₆) alkyl, C₁₋₆ alkoxy, (C₁₋₆) alkoxy(C₁₋₆)alkyl, C₂₋₆alkylcarbonyl, C₂₋₆ alkoxycarbonyl, (C₂₋₆) alkoxycarbonyl-amino-C₁₋₆alkyl, phosphate(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, oxo,(C₁₋₆)alkylsulphoximinyl, (C₁₋₆)alkylsulphinyl-amino-,di(C₁₋₆)alkylamino (C₁₋₆)alkyl, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl,di(C₁₋₆)alkenylamino (C₁₋₆)alkyl, (C₂)alkylcarbonylamino(Calkyl, C₁₋₆alkylsulphonyl-amino-C₁₋₆ alkyl, tetrahydrofuranyl, sulphate(C₁₋₆)alkyl,and carboxy-(C₁₋₆)alkyl-carbonyloxy-(C₁₋₆)alkyl; R² represents hydrogenor halogen; R³ and R⁴ independently represent hydrogen, halogen ortrifluoromethyl; or C₁₋₆ alkyl; R⁵ represents halogen, —OR^(a),difluoromethoxy or trifluoromethoxy; R⁶ represents hydrogen, halogen ortrifluoromethyl; R⁷ represents hydrogen or trifluoromethyl; R⁸represents hydrogen, halogen or trifluoromethyl; R¹² represents hydrogenor C₁₋₆ alkyl; R^(a) represents C₁₋₆ alkyl; R^(f) represents hydrogen;or C₁₋₆ alkyl, which group may be optionally substituted by one or moresubstituents selected from halogen or C₁₋₆ alkyl; and R^(g) representshydrogen; or C₁₋₆ alkyl, —CO—(C₁₋₆)alkyl, —SO₂—(C₁₋₆)alkyl.—CO—(C₃₋₇)heterocycloalkyl, —SO₂—(C₃₋₇)cycloalkyl, —SO₂-aryl,—SO₂-heteroaryl, heteroaryl or (C₂₋₆)alkoxycarbonyl, any of which groupsmay be optionally substituted by one or more substituents selected fromhalogen or C₁₋₆ alkyl
 5. A compound represented by formula (IC), or anN-oxide thereof, or a pharmaceutically acceptable salt thereof,

wherein —X-Q- represents —O—, —O—C(O)—, —O—C(CH—CN)—, —S—, —SO-, —SO₂—;or —N(R^(g))—, —N(R^(f))—CO—, —N(R^(f))—SO₂—, —O—CH₂—, —CH₂—S—,—CH₂—SO-, —CH₂—SO₂—, —N(R^(g))—CH₂—, —N(R^(f))—C(S)—, —N═S(O)(CH₃)—,—O—C(═CH₂)— or —S(═N—CN)—, any of which groups may be optionallysubstituted by one or more substituents selected from fluoro, methyl,carboxy, trifluoromethyl, methylcarbonyl, deuterated methyl,ethoxycarbonyl, hydroxyisopropyl, and hydroxymethyl; Z representsmethylene; R¹ represents halogen or cyano; or aryl, heteroaryl,(C₃₋₇)cycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl-heteroaryl,(C⁴⁻⁹)heterobicycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl,(C₃₋₇)heterocycloalkenyl, or (C₃₋₇)heterocycloalkenyl-aryl, any of whichgroups may be optionally substituted by one or more substituentsselected from halogen, cyano, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl,difluoromethyl, trifluoromethyl, hydroxy, (hydroxy)(C₁₋₆)alkyl, amino,(amino)(C₁₋₆) alkyl, C₁₋₆ alkoxy, (C₁₋₆) alkoxy(C₁₋₆)alkyl, C₂₋₆alkylcarbonyl, C₂₋₆ alkoxycarbonyl, (C₂₋₆) alkoxycarbonyl-amino-C₁₋₆alkyl, phosphate(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, oxo,(C₁₋₆)alkylsulphoximinyl, (C₁₋₆)alkylsulphinyl-amino-,di(C₁₋₆)alkylamino (C₁₋₆)alkyl, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl,di(C₁₋₆)alkenylamino (C₁₋₆)alkyl, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl,C₁₋₆ alkylsulphonyl-amino-C₁₋₆ alkyl, tetrahydrofuranyl,sulphate(C₁₋₆)alkyl, and carboxy-(C₁₋₆)alkyl-carbonyloxy-(C₁₋₆)alkyl; R²represents hydrogen or halogen; R³ and R⁴ independently representhydrogen, halogen or trifluoromethyl; or C₁₋₆ alkyl; R⁵ representshalogen, —OR^(a), difluoromethoxy or trifluoromethoxy; R⁶ representshydrogen, halogen or trifluoromethyl; R⁷ represents hydrogen ortrifluoromethyl; R⁸ represents hydrogen, halogen or trifluoromethyl; R¹²represents hydrogen or C₁₋₆ alkyl; R^(a) represents C₁₋₆ alkyl; R^(f)represents hydrogen; or C₁₋₆ alkyl, which group may be optionallysubstituted by one or more substituents selected from halogen or C₁₋₆alkyl; and R^(g) represents hydrogen; or C₁₋₆ alkyl, —CO—(C₁₋₆)alkyl,—SO₂—(C₁₋₆)alkyl. —CO—(C₃₋₇)heterocycloalkyl, —SO₂—(C₃₋₇)cycloalkyl,—SO₂-aryl, —SO₂-heteroaryl, heteroaryl or (C₂₋₆)alkoxycarbonyl, any ofwhich groups may be optionally substituted by one or more substituentsselected from halogen or C₁₋₆ alkyl.
 6. (canceled)
 7. A compound asclaimed in claim 4 wherein —X-Q- include —O—, —O—CO—, —O—C(CH-13 CN)—,—S—, —SO—, —SO₂—, —NH—, —N(CO—CH₃)—, —N(SO₂—CH₃)—,—N(CH₂—CO—O—CH₂—CH₃)—,—N[(CO—CH₂-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)]-,—N[CO-(azetidin-3-yl)]-, —N[CO-(methylsulphonyl)azetidin-3-yl)]-,—N(CH₂—COOH), —N[(tert-butyl)(dimethyl)silyloxyethyl]-,—N(SO₂-pyridine-3-yl)-, —N—(SO₂-cyclopropyl)-, —N(CH₃)—CH₂—,—N(CH₂—CH₂—OH)—, —N(SO₂-phenyl)-, —N[SO₂-(6-methoxy-pyridin-3-yl)]-,—NH—CO—, —N(CH₃)—CO—, —N(CH₂CH₃)—CO—, —N(CH(CH₃)₂)—CO—,—N(CH₂—COOH)—CO—, —N(CH₂—CF₃)—CO—, —N(CH₂—CH₂-OH)—CO—,—N(CH₂—C(OH)(CH₃)₂)—CO—, —N(CD₃)—CO—, —NH—CH₂—, —N(CH₂—COOH)—CH₂—,—NH—CH(CF₃)—, —NH—CH(CH₃)—, —NH—C(S)—, —N(CO—CH₃)—CH(CH₃)—,—N(SO₂—CH₃)—CH₂—, —N(CO—CH₃)—CH(CH₃)—, —N═S(O)(CH₃)—, —O—CH(CF₃)—,—CH(COOC₂H₅)—S—, —CH₂—S(O)—, —CH₂—S(O)₂—, —CH(C(OH)(CH₃)₂)—S—,—CH(CH₂OH)—S—, —O—C(═CH₂)—, —N[S(O)₂-(pyridin-1H-2-one)], —NH—S(O)₂—,—N(pyrimidinyl)-, —N(COOC₂H₅)—, —S(═N—CN)—, —N(SO₂—CH₃)— or—N(C₂H₅)—CO—.
 8. A compound as claimed in claim 4 wherein —X-Q-represents represents —N(R^(f))—C(O).
 9. A compound of formula (IIB) oran N-oxide thereof, or a pharmaceutical acceptable salt thereof,

wherein R¹ represents halogen or cyano; or aryl, heteroaryl,(C₃₋₇)cycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl-heteroaryl,(C⁴⁻⁹)heterobicycloalkyl-heteroaryl, (C₃₋₇)heterocycloalkyl,(C₃₋₇)heterocycloalkenyl, or (C₃₋₇)heterocycloalkenyl-aryl, any of whichgroups may be optionally substituted by one or more substituentsselected from halogen, cyano, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl,difluoromethyl, trifluoromethyl, hydroxy, (hydroxy)(C₁₋₆)alkyl, amino,(amino)(C₁₋₆) alkyl, C₁₋₆ alkoxy, (C₁₋₆) alkoxy(C₁₋₆)alkyl, C₂₋₆alkylcarbonyl, C₂₋₆ alkoxycarbonyl, (C₂₋₆) alkoxycarbonyl-amino-C₁₋₆alkyl, phosphate(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, oxo,(C₁₋₆)alkylsulphoximinyl, (C₁₋₆)alkylsulphinyl-amino-,di(C₁₋₆)alkylamino (C₁₋₆)alkyl, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl,di(C₁₋₆)alkenylamino (C₁₋₆)alkyl, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl,C₁₋₆ alkylsulphonyl-amino-C₁₋₆ alkyl, tetrahydrofuranyl,sulphate(C₁₋₆)alkyl, and carboxy-(C₁₋₆)alkyl-carbonyloxy-(C₁₋₆)alkyl; R²represents hydrogen or halogen; R³ and R⁴ independently representhydrogen, halogen or trifluoromethyl; or C₁₋₆ alkyl; R⁵ representshalogen, —OR^(a), difluoromethoxy or trifluoromethoxy; R⁶ representshydrogen, halogen or trifluoromethyl; R⁷ represents hydrogen ortrifluoromethyl; R⁸ represents hydrogen, halogen or trifluoromethyl;R^(a) represents C₁₋₆ alkyl; and R^(f) represents hydrogen; or C₁₋₆alkyl, which group may be optionally substituted by one or moresubstituents selected from halogen or C₁₋₆ alkyl.
 10. (canceled)
 11. Acompound as claimed in claim 4 wherein R¹ represents aryl or heteroaryl,either of which groups may be optionally substituted by one or moresubstituents selected from halogen, cyano, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl,difluoromethyl, trifluoromethyl, hydroxy, (hydroxy)(C₁₋₆)alkyl, amino,(amino)(C₁₋₆) alkyl, C₁₋₆ alkoxy, alkoxy(C₁₋₆)alkyl, C₂₋₆ alkylcarbonyl,C₂₋₆ alkoxycarbonyl, (C₂₋₆) alkoxycarbonyl-amino-C₁₋₆ alkyl,phosphate(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, oxo,(C₁₋₆)alkylsulphoximinyl, (C₁₋₆)alkylsulphinyl-amino-,di(C₂)alkylcarbonylamino(C₁₋₆)alkyl, di(C₁₋₆)alkenylamino (C₁₋₆)alkyl,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl-amino-C₁₋₆alkyl, tetrahydrofuranyl, sulphate(C₁₋₆)alkyl, andcarboxy-(C₁₋₆)alkyl-carbonyloxy-(C₁₋₆)alkyl.
 12. (canceled)
 13. Acompound as claimed in claim 4 wherein R³ represents hydrogen ortrifluoromethyl.
 14. A compound as claimed in claim 4 wherein R⁴represents hydrogen or trifluoromethyl.
 15. (canceled)
 16. (canceled)17. (canceled)
 18. (canceled)
 19. A compound as claimed in claim 4represented by formula (IIB-A), or an N-oxide thereof, or apharmaceutically acceptable salt thereof,

wherein R¹ represents aryl or heteroaryl, either of which groups may beoptionally substituted by one or more substituents selected fromhalogen, cyano, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl, difluoromethyl,trifluoromethyl, hydroxy, (hydroxy)(C₁₋₆)alkyl, amino, (amino)(C₁₋₆)alkyl, C₁₋₆ alkoxy, (C₁₋₆) alkoxy(C₁₋₆)alkyl, C₂₋₆ alkylcarbonyl, C₂₋₆alkoxycarbonyl, (C₂₋₆) alkoxycarbonyl-amino-C₁₋₆ alkyl,phosphate(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, oxo,(C₁₋₆)alkylsulphoximinyl, (C₁₋₆)alkylsulphinyl-amino-,di(C₁₋₆)alkylamino (C₁₋₆)alkyl, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl,di(C₁₋₆)alkenylamino-(C₁₋₆)alkyl, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl,C₁₋₆ alkylsulphonyl-amino-C₁₋₆ alkyl, tetrahydrofuranyl,sulphate(C₁₋₆)alkyl, and carboxy-(C₁₋₆)alkyl-carbonyloxy-(C₁₋₆)alkyl.20. (canceled)
 21. A compound as claimed in claim 19 represented byformula (IIB-AB-A), an N-oxide thereof, or pharmaceutically acceptablesalt thereof,

wherein R⁹ represents amino(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, or (C₁₋₆)alkoxy(C₁₋₆)alkyl; R¹⁰ represents hydrogen or C₁₋₆ alkyl; W represents Nor C—H.
 22. A compound as claimed in claim 21 wherein W represents N.23. A compound as claimed in claim 21 wherein R¹⁰ represents hydrogen.24. A compound as claimed in claim 21 wherein R⁹ represents2-hydroxy-prop-2-yl.
 25. A compound as claimed in claim 4 wherein: (i)R² represents fluoro; and/or (ii) R⁵ represents difluoromethoxy; and/or(iii) R^(f) represents hydrogen.
 26. A compound as claimed in claim 5wherein: (i) R² represents fluoro; and/or (ii) R⁵ representsdifluoromethoxy; and/or (iii) R^(f) represents hydrogen.
 27. A compoundas claimed in claim 9 wherein: (i) R² represents fluoro; and/or (ii) R⁵represents difluoromethoxy; and/or (iii) R^(f) represents hydrogen. 28.(canceled)
 29. (canceled)
 30. (canceled)
 31. (canceled)
 32. Apharmaceutical composition comprising a compound of formula (TB) asclaimed in claim 4, or an N-oxide thereof, or a pharmaceuticallyacceptable salt thereof, in association with a pharmaceuticallyacceptable carrier.
 33. (canceled)
 34. (canceled)
 35. A method for thetreatment and/or prevention of disorders for which the administration ofa modulator of TNFα function is indicated which comprises administeringto a patient in need of such treatment an effective amount of a compoundof formula (IB) as defined in claim 4, or an N-oxide thereof, or apharmaceutically acceptable salt thereof.
 36. A method for the treatmentand/or prevention of an inflammatory or autoimmune disorder, aneurological or neuro-degenerative disorder, pain or a nociceptivedisorder, a cardiovascular disorder, a metabolic disorder, an oculardisorder, or an oncological disorder, which comprises administering to apatient in need of such treatment an effective amount of a compound offormula (IB) as defined in claim 4 or an N-oxide thereof, or apharmaceutically acceptable salt thereof.
 37. A compound as claimed inclaim 1 wherein: —X-Q- represents —N(R^(f))—CO—, which may be optionallysubstituted by one or more substituents selected from fluoro, methyl,carboxy, trifluoromethyl, methylcarbonyl, deuterated methyl,ethoxycarbonyl, hydroxyisopropyl, and hydroxymethyl; R¹ representsheteroaryl, which may be optionally substituted by one or moresubstituents selected from halogen, cyano, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl,difluoromethyl, trifluoromethyl, hydroxy, (hydroxy)(C₁₋₆)alkyl, amino,(amino)(C₁₋₆) alkyl, C₁₋₆ alkoxy, (C₁₋₆) alkoxy(C₁₋₆)alkyl, C₂₋₆alkylcarbonyl, C₂₋₆ alkoxycarbonyl, (C₂₋₆) alkoxycarbonyl-amino-C₁₋₆alkyl, phosphate(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, oxo,(C₁₋₆)alkylsulphoximinyl, (C₁₋₆)alkylsulphinyl-amino-,di(C₁₋₆)alkylamino (C₁₋₆)alkyl, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl,di(C₁₋₆)alkenylamino (C₁₋₆)alkyl, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl,C₁₋₆ alkylsulphonyl-amino-C₁₋₆ alkyl, tetrahydrofuranyl,sulphate(C₁₋₆)alkyl, and carboxy-(C₁₋₆)alkyl-carbonyloxy-(C₁₋₆)alkyl; R²represents hydrogen; R³ and R⁴ independently represent hydrogen; R⁵represents difluoromethoxy; R⁶ represents hydrogen; R⁷ representshydrogen; R⁸ represents hydrogen; R¹² represents C₁₋₆ alkyl; and R^(f)represents hydrogen; or C₁₋₆ alkyl, which group may be optionallysubstituted by one or more substituents selected from halogen or C₁₋₆alkyl.
 38. A compound as claimed in claim 1 wherein: —X-Q- is—N(R^(f))—CO—; R¹ represents heteroaryl, which may be optionallysubstituted by one or more substituents selected from(hydroxy)(C₁₋₆)alkyl and (amino)(C₁₋₆) alkyl; R² represents hydrogen; R³and R⁴ independently represent hydrogen; R⁵ represents difluoromethoxy;R⁶ represents hydrogen; R⁷ represents hydrogen; R⁸ represents hydrogen;R¹² represents C₁₋₆ alkyl; and R^(f) represents hydrogen; or C₁₋₆ alkyl.39. A compound as claimed in claim 1 selected from:(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;(7R,14R)-1-(difluoromethoxy)-6-ethyl-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;and(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one.40. A pharmaceutical composition comprising a compound of formula (IC)as claimed in claim 5, or an N-oxide thereof, or a pharmaceuticallyacceptable salt thereof, in association with a pharmaceuticallyacceptable carrier.
 41. A method for the treatment and/or prevention ofdisorders for which the administration of a modulator of TNFα functionis indicated which comprises administering to a patient in need of suchtreatment an effective amount of a compound of formula (IC) as definedin claim 5, or an N-oxide thereof, or a pharmaceutically acceptable saltthereof.
 42. A method for the treatment and/or prevention of aninflammatory or autoimmune disorder, a neurological orneuro-degenerative disorder, pain or a nociceptive disorder, acardiovascular disorder, a metabolic disorder, an ocular disorder, or anoncological disorder, which comprises administering to a patient in needof such treatment an effective amount of a compound of formula (IC) asdefined in claim 5, or an N-oxide thereof, or a pharmaceuticallyacceptable salt thereof.